Carboline carboxamide compounds useful as kinase inhibitors

ABSTRACT

Compounds having formula (I), and enantiomers, and diastereomers, stereoisomers, pharmaceutically-acceptable salts thereof, formula (I) are useful as kinase modulators, including Btk modulation.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Ser.No. 61/355,275, filed Jun. 16, 2010, which is incorporated herein in itsentirety.

FIELD OF THE INVENTION

This invention relates to carboline carboxamide compounds useful askinase inhibitors, including the modulation of Bruton's tyrosine kinase(Btk) and other Tec family kinases such as Itk. Provided herein arecarboline carboxamide compounds, compositions comprising such compounds,and methods of their use. The invention further pertains topharmaceutical compositions containing at least one compound accordingto the invention that are useful for the treatment of conditions relatedto kinase modulation and methods of inhibiting the activity of kinases,including Btk and other Tec family kinases such as Itk, in a mammal.

BACKGROUND OF THE INVENTION

Protein kinases, the largest family of human enzymes, encompass wellover 500 proteins. Btk is a member of the Tec family of tyrosinekinases, and is a regulator of early B-cell development, as well asmature B-cell activation, signaling and survival.

B-cell signaling through the B-cell receptor (BCR) leads to a wide rangeof biological outputs, which in turn depend on the developmental stageof the B-cell. The magnitude and duration of BCR signals must beprecisely regulated. Aberrant BCR-mediated signaling can causedisregulated B-cell activation and/or the formation of pathogenicauto-antibodies leading to multiple autoimmune and/or inflammatorydiseases. Mutation of Btk in humans results in X-linkedagammaglobulinaemia (XLA). This disease is associated with the impairedmaturation of B-cells, diminished immunoglobulin production, compromisedT-cell-independent immune responses and marked attenuation of thesustained calcium signal upon BCR stimulation.

Evidence for the role of Btk in allergic disorders and/or autoimmunedisease and/or inflammatory disease has been established inBtk-deficient mouse models. For example, in standard murine preclinicalmodels of systemic lupus erythematosus (SLE), Btk deficiency has beenshown to result in a marked amelioration of disease progression.Moreover, Btk deficient mice are also resistant to developingcollagen-induced arthritis and are less susceptible toStaphylococcus-induced arthritis.

A large body of evidence supports the role of B-cells and the humoralimmune system in the pathogenesis of autoimmune and/or inflammatorydiseases. Protein-based therapeutics (such as RITUXAN®) developed todeplete B-cells, represent an important approach to the treatment of anumber of autoimmune and/or inflammatory diseases. Because of Btk's rolein B-cell activation, inhibitors of Btk can be useful as inhibitors ofB-cell mediated pathogenic activity (such as autoantibody production).

Btk is also expressed in mast cells and monocytes and has been shown tobe important for the function of these cells. For example, Btkdeficiency in mice is associated with impaired IgE-mediated mast cellactivation (marked diminution of TNF-alpha and other inflammatorycytokine release), and Btk deficiency in humans is associated withgreatly reduced TNF-alpha production by activated monocytes.

Thus, inhibition of Btk activity can be useful for the treatment ofallergic disorders and/or autoimmune and/or inflammatory diseasesincluding, but not limited to: SLE, rheumatoid arthritis, multiplevasculitides, idiopathic thrombocytopenic purpura (ITP), myastheniagravis, allergic rhinitis, multiple sclerosis (MS), transplantrejection, type I diabetes, membranous nephritis, inflammatory boweldisease, autoimmune hemolytic anemia, autoimmune thyroiditis, cold andwarm agglutinin diseases, Evan's syndrome, hemolytic uremicsyndrome/thrombotic thrombocytopenic purpura (HUS/TTP), sarcoidosis,Sjögren's syndrome, peripheral neuropathies (e.g., Guillain-Barresyndrome), pemphigus vulgaris, and asthma.

In addition, Btk has been reported to play a role in controlling B-cellsurvival in certain B-cell cancers. For example, Btk has been shown tobe important for the survival of BCR-Abl-positive B-cell acutelymphoblastic leukemia cells. Thus inhibition of Btk activity can beuseful for the treatment of B-cell lymphoma and leukemia.

In view of the numerous conditions that are contemplated to benefit bytreatment involving modulation of protein kinases, it is immediatelyapparent that new compounds capable of modulating protein kinases suchas Btk and methods of using these compounds should provide substantialtherapeutic benefits to a wide variety of patients.

Inhibitors of protein kinases are widely sought and a number ofpublications report compounds effective in modulating protein kinases.For example, patent publications WO 2005/047290, WO 2005/014599, WO2005/005429, WO 2006/099075, WO 2006/053121, and US 2006/0183746disclose certain imidazopyrazine compounds that are said to inhibitprotein kinase activity, including Btk activity. Patent publication WO2008/033858 discloses methods of inhibiting Btk activity with variousBtk binding chemical compounds. Patent publication US 2006/0084650discloses that fused heterocyclic compounds exemplified byimidazopyrimidines and pyrrolotriazines may be used as protein kinaseinhibitors. In addition, new imidazopyridazine and imidazotriazinecompounds are disclosed in WO 2007/038314 (published Apr. 5, 2007) andWO 2008/0045536 (published Feb. 21, 2008), both of which are assigned tothe present assignee. Also assigned to the present assignee, WO2010/080481 (published Jul. 15, 2010) discloses certain carbazolecarboxamides useful as Btk inhibitors.

The present invention relates to a new class of substituted carbolinecarboxamide compounds found to be effective inhibitors of proteinkinases including Btk and other Tec family kinases such as Itk.

SUMMARY OF THE INVENTION

Modulators of kinase activity which may generally be described assubstituted β-carboline carboxamides, γ-aza-β-carboline carboxamides,and related compounds are provided herein.

The invention is directed to compounds of Formula (I), or stereoisomers,tautomers, pharmaceutically acceptable salts, solvates or prodrugsthereof, useful as inhibitors of Btk in the treatment of proliferativediseases, allergic diseases, autoimmune diseases and inflammatorydiseases.

The present invention also provides processes and intermediates formaking the compounds of the present invention or stereoisomers,tautomers, pharmaceutically acceptable salts, solvates, or prodrugsthereof.

The present invention also provides pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and at least one of thecompounds of the present invention or stereoisomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrugs thereof.

The present invention also provides methods for inhibition of Btkcomprising administering to a host in need of such treatment atherapeutically effective amount of at least one of the compounds of thepresent invention or stereoisomers, tautomers, pharmaceuticallyacceptable salts, solvates, or prodrugs thereof.

The present invention also provides methods for treating proliferativediseases, allergic diseases, autoimmune diseases and inflammatorydiseases, comprising administering to a host in need of such treatment atherapeutically effective amount of at least one of the compounds of thepresent invention or stereoisomers, tautomers, pharmaceuticallyacceptable salts, solvates, or prodrugs thereof.

The present invention also provides the compounds of the presentinvention or stereoisomers, tautomers, pharmaceutically acceptablesalts, solvates, or prodrugs thereof, for use in therapy.

The present invention also provides the use of the compounds of thepresent invention or stereoisomers, tautomers, pharmaceuticallyacceptable salts, solvates, or prodrugs thereof, for the manufacture ofa medicament for the treatment of cancers.

These and other features of the invention will be set forth in theexpanded form as the disclosure continues.

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

Provided herein is at least one chemical entity chosen from compounds offormula (I):

or enantiomers, diastereomers, stereoisomers, prodrugs, orpharmaceutically-acceptable salts thereof, wherein

X is CR³ or N;

Y is CR³ or N;

Z is CD¹ or N;

W is CD² or N;

— is an optional bond; provided when the two optional bonds are absent,Z is CHD¹, W is ND² or Z is ND¹, W is CHD²;

A is C₃₋₁₀ carbocycle substituted with 0-3 B, C₆₋₁₀ mono- or bicyclicaryl substituted with 0-3 B, a 5-14 membered heterocyclyl containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 B, a 5-10membered heteroaryl containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-3 B;

B is R¹, halogen, cyano, nitro, —OR¹, —C(═O)R¹, —C(═O)OR¹, —C(═O)NR¹¹R¹,—S(═O)₂R¹, —NR¹¹C(═O)R¹, —NR¹¹C(═O)NR¹¹R¹, —NR¹¹C(═O)OR¹, —N(C(═O)OR¹)₂,—NR¹¹S(═O)₂R¹, —N(S(═O)₂R¹)₂, or —NR¹¹R¹;

R¹ is hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(1a), C₁₋₆ haloalkyl,C₂₋₆ alkenyl substituted with 0-3 R^(1a), C₂₋₆ alkynyl substituted with0-3 R^(1a), C₃₋₁₀ cycloalkyl substituted with 0-3 R^(1a), C₆₋₁₀ arylsubstituted with 0-3 R^(1a), a 5-10 membered heterocyclyl containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R^(1a), a5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O,and S, substituted with 0-3 R^(1a);

R^(1a) is hydrogen, ═O, F, Cl, Br, OCF₃, CF₃, CHF₂, CN, NO₂,—(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(p)R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substitutedwith 0-2 R^(a), C₁₋₆ haloalkyl, —(CH₂)_(r)-3-14 membered carbocyclesubstituted with 0-1 R^(a), or —(CH₂)_(r)-5-7 membered heterocyclecomprising carbon atoms and 1-4 heteroatoms selected from N, O, andS(O)_(p) substituted with 0-1 R^(a);

D¹ and D² are independently R², halogen, —(C(R¹¹)₂)_(r)R², —OR²,—C(═O)R², —C(═O)OR², —C(═O)NR¹¹R², —S(═O)₂R², —S(═O)R², —SR²,—NR¹¹C(═O)R², —NR¹¹C(═O)NR¹¹R², —NR¹¹C(═O)OR², —NR¹¹S(═O)₂R², —NR¹¹R²,—C(═O)NR¹¹OR², —OC(═O)OR², —O¹C(═O)R², or CH═N—OH; alternatively D¹ andD² join to form —O—CH₂—O—;

D³ is hydrogen, halogen, C₁₋₃ alkyl, C₁₋₃ alkoxy, or CN;

R² is hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(2a), C₂₋₆ alkenylsubstituted with 0-3 R^(2a), C₂₋₆ alkynyl substituted with 0-3 R^(2a),C₃₋₁₀ cycloalkyl substituted with 0-3 R^(2a), C₆₋₁₀ aryl substitutedwith 0-3 R^(2a), a 5-10 membered heterocyclyl containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(2a), a 5-10 memberedheteroaryl containing 1-4 heteroatoms selected from N, O, and S,substituted with 0-3 R^(2a);

R^(2a) is hydrogen, ═O, F, Cl, Br, OCF₃, CN, NO₂, —(CH₂)_(r)OR^(b),—(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b), —(CH₂)_(r)C(O)OR^(b),—(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹, —(CH₂)_(r)C(O)NR¹¹R¹¹,—(CH₂)_(r)NR^(b)C(O)R^(c), —(CH₂)_(r)NR^(b)C(O)OR^(c),—NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), —S(O)R^(c),—S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-2 R^(a), C₁₋₆ haloalkyl,—(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a), or—(CH₂)_(r)-5-7 membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p) substituted with 0-2 R^(a);

R¹¹ is independently hydrogen or C₁₋₄ alkyl substituted with 0-1 R^(f),CH₂-phenyl, or —(CH₂)_(r)-5-7 membered heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, O, and S(O)_(p);

alternatively, R¹¹ along with another R¹¹, R¹, or R² on the samenitrogen atom may join to form an optionally substituted azetidinyl,pyrrolidinyl, piperidinyl, morpholinyl, or 4-(C₁₋₆ alkyl)piperazinyl;

R³ is hydrogen or C₁₋₆ alkyl;

R^(a) is hydrogen, F, Cl, Br, OCF₃, CF₃, CHF₂, CN, NO₂,—(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(p)R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substitutedwith 0-1 R^(f), C₁₋₆ haloalkyl, —(CH₂)_(r)-3-14 membered carbocycle, or—(CH₂)_(r)-5-7 membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), alternatively two R^(a) onadjacent or the same carbon atom form a cyclic acetal of the formula—O—(CH₂)_(n)—O—, or —O—CF₂—O—, wherein n is selected from 1 or 2;

R^(b) is hydrogen, C₁₋₆ alkyl substituted with 0-2 R^(d), C₁₋₆haloalkyl, C₃₋₆ cycloalkyl substituted with 0-2 R^(d), or(CH₂)_(r)-phenyl substituted with 0-2 R^(d);

R^(c) is C₁₋₆ alkyl substituted with 0-1 R^(f), C₃₋₆ cycloalkyl, or(CH₂)_(r)-phenyl substituted with 0-1 R^(f);

R^(d) is hydrogen, F, Cl, Br, OCF₃, CF₃, CN, NO₂, —OR^(e),—(CH₂)_(r)C(O)R^(c), —NR^(e)R^(e), —NR^(e)C(O)OR^(c), C₁₋₆ alkyl, or(CH₂)_(r)-phenyl;

R^(e) is hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, or (CH₂)_(r)-phenyl;

R^(f) is hydrogen, halo, NH₂, OH, or OCH₃;

r is 0, 1, 2, 3, or 4; and

p is 0, 1, or 2.

In another embodiment there are provided compounds of formula (I),wherein

D¹ and D² are independently R², —(CH₂)_(r)R², —OR², —C(═O)R², —C(═O)OR²,—C(═O)NR¹¹R², —S(═O)₂R², —S(═O)R², SR², —NR¹¹C(═O)R², —NR¹¹C(═O)NR¹¹R²,—NR¹¹C(═O)OR², —NR¹¹S(═O)₂R², or —NR¹¹R²;

R² is hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(2a), C₂₋₆ alkenylsubstituted with 0-3 R^(2a), C₃₋₁₀ cycloalkyl substituted with 0-3R^(2a), —C₆₋₁₀ aryl substituted with 0-3 R^(2a), a 5-10 memberedheterocyclyl containing 1-4 heteroatoms selected from N, O, and S,substituted with 0-3 R^(2a), a 5-10 membered heteroaryl containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R^(2a);

R^(2a) is hydrogen, ═O, F, Cl, Br, OCF₃, CF₃, CHF₂, CN, NO₂, OR^(b),SR^(b), —C(O)R^(b), —C(O)OR^(b), —OC(O)R^(b), —NR¹¹R¹¹, —C(O)NR¹¹R¹¹,—NR^(b)C(═O)R^(c), —NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹,—S(═O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p))R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆alkyl substituted with 0-2 R^(a), —(CH₂)_(r)-3-14 membered carbocyclesubstituted with 0-1 R^(a), wherein the carbocycle is cyclopropyl,cyclobutyl, cyclopentyl or cyclohexyl; or —(CH₂)_(r)-5-7 memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,O, and S(O)_(p) substituted with 0-2 R^(a); and

r is 0, 1, or 2.

In another embodiment there are provided compounds of formula (I),wherein

A is C₃₋₁₀ carbocycle substituted with 0-3 B, C₆₋₁₀ mono- or bicyclicaryl substituted with 0-3-B;

B is R¹, halogen, cyano, nitro, —OR¹, —C(═O)R¹, —C(═O)OR¹, —C(═O)NR¹¹R¹,—S(═O)₂R¹, —NR¹¹C(═O)R¹, —NR¹¹C(═O)NR¹¹R¹, —NR¹¹S(═O)₂R¹, —N(S(═O)₂R¹)₂,or —NR¹¹R¹; and

R¹ is hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(1a), C₁₋₆ haloalkyl,C₆₋₁₀ aryl substituted with 0-3 R^(1a), a 5-10 membered heterocyclylcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-3 R^(1a), a 5-10 membered heteroaryl containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(1a).

In another embodiment there are provided compounds of formula (I),wherein

R² is hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(2a), ethenyl, C₃₋₁₀cycloalkyl substituted with 0-3 R^(2a), C₆₋₁₀ aryl substituted with 0-3R^(2a), a 5-10 membered heterocyclyl containing 1-4 heteroatoms selectedfrom N, O, and S, substituted with 0-3 R^(2a), wherein the heterocyclylis pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl,tetrahydrofuranyl, tetrahydropyranyl; a 5-10 membered heteroarylcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-3 R^(2a), wherein the heteroaryl is pyrimidinyl, imidazolyl,pyrazinyl, thiadiazolyl, pyridinyl, quinolinyl, isoquinolinyl, orthiazolyl.

In another embodiment there are provided compounds of formula (I),wherein

A is C₆ carbocycle substituted with 0-3 B, C₆₋₁₀ mono- or bicyclic arylsubstituted with 0-3-B; and

R¹ is hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(1a), C₁₋₆ haloalkyl,C₆₋₁₀ aryl substituted with 0-3 R^(1a), a 5-10 membered heterocyclylcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-3 R^(1a), wherein the heterocyclyl is isoquinolin-1(2H)-one,isoindolinyl, isoindoline-1,3-dione, quinolinyl, quinazolinyl,quinazolin-4(3H)-one, or pyrido[3,2-d]pyrimidine.

In another embodiment there are provided compounds according to formula(Ia), (Ib) or (Ic):

In another embodiment there are provided compounds according to formula(Id) or (Ie):

In another embodiment there are provided compounds according to formula(If) or (Ig):

In another embodiment there are provided compounds of formula (I),wherein

R^(a) is hydrogen, F, Cl, Br, OCF₃, CF₃, CHF₂, CN, NO₂, —OR^(b),—SR^(b), —C(O)R^(b), —C(O)OR^(b), —OC(O)R^(b), —NR¹¹R¹¹, —C(O)NR¹¹R¹¹,—NR^(b)C(O)R^(c), —NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹,—S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆alkyl substituted with 0-1 R^(f), C₁₋₆ haloalkyl, —(CH₂)_(r)-3-6membered carbocycle, or —(CH₂)_(r)-5-7 membered heterocycle comprisingcarbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p),wherein the heterocycle is pyrrolidinyl, pyrrolyl, pyrazolyl,imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furyl,thienyl, pyridyl, pyrazinyl, pyrimidinyl, morpholinyl, thiamorpholinyl,triazolyl, indolyl, benzothiazolyl, benzoxazolyl, benzothienyl,quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, benzimidazolyl,benzopyranyl, benzofuryl, benzisothiazolyl, benzisoxazolyl,benzodiazinyl, or benzofurazanyl;

R^(b) is hydrogen, C₁₋₆ alkyl substituted with 0-2 R^(d), C₁₋₆haloalkyl, C₃₋₆ cycloalkyl substituted with 0-2 R^(d), or(CH₂)_(r)-phenyl substituted with 0-2 R^(d);

R^(c) is C₁₋₆ alkyl substituted with 0-1 R^(f), C₃₋₆ cycloalkyl, or(CH₂)_(r)-phenyl substituted with 0-1 R^(f);

R^(d) is hydrogen, F, Cl, Br, OCF₃, CF₃, CN, NO2, —OR^(e), —C(O)R^(c),—NR^(e)R^(e), —NR^(e)C(O)OR^(c), C₁₋₆ alkyl, or (CH₂)_(r)-phenyl;

R^(e) is hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, or (CH₂)_(r)-phenyl;

R^(f) is hydrogen, halo, or NH₂; and

r is 0 or 1.

In another embodiment there are provided compounds of formula (I),wherein

R^(a) is hydrogen, F, Cl, Br, OCF₃, CF₃, CHF₂, CN, NO₂, —OR^(b),—SR^(b), —C(O)R^(b), —C(O)OR^(b), —OC(O)R^(b), —NR¹¹R¹¹, —C(O)NR¹¹R¹¹,—NR^(b)C(O)R^(c), —NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹,—S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆alkyl, C₁₋₆ haloalkyl, —(CH₂)_(r)-3-6 membered carbocycle phenyl, or—(CH₂)_(r)-5-7 membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein the heterocycle isthiazolyl, pyridinyl, piperidinyl, morpholinyl, piperazinyl,pyrrolidinyl, pyrrolidin-one;

R^(b) is hydrogen, C₁₋₆ alkyl substituted with 0-2 R^(d), C₁₋₆haloalkyl, C₃₋₆ cycloalkyl substituted with 0-2 R^(d), or(CH₂)_(r)-phenyl substituted with 0-2 R^(d);

R^(c) is C₁₋₆ alkyl, C₃₋₆ cycloalkyl, or (CH₂)_(r)-phenyl;

R^(d) is hydrogen, F, Cl, Br, OCF₃, CF₃, CN, NO2, —OR^(e), —C(O)R^(c),—NR^(e)R^(e), —NR^(e)C(O)OR^(c), C₁₋₆ alkyl, or (CH₂)_(r)-phenyl; and

R^(e) is hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, or (CH₂)_(r)-phenyl.

In another embodiment there are provided compounds of formula (I),wherein

A is C₆ carbocycle substituted with 0-3 B, wherein the carbocycle iscyclohexyl or cyclohexenyl, C₆₋₁₀ mono- or bicyclic aryl substitutedwith 0-3-B, wherein the aryl group is phenyl or naphthyl;

B is R¹, halogen, —C(═O)OR¹, —S(═O)₂R¹, —NR¹¹C(═O)R¹, —NR¹¹C(═O)NR¹¹R¹,—NR¹¹S(═O)₂R¹, N(S(═O)₂R¹)₂, or —NR¹¹R¹;

R¹ is hydrogen, trifluoromethyl, C₁₋₄ alkyl substituted with 0-1 R^(1a),phenyl substituted with 0-3 R^(1a), a 5-10 membered heteroarylcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-3 R^(1a), wherein the heteroaryl is pyridyl or thiazolyl;

one of D¹ and D² is R², —C(═O)R², —OR², —C(═O)NR¹¹R², NR¹¹C(═O)R²,NR¹¹C(═O)NR¹¹R², NR¹¹S(═O)₂R², or —NR¹¹R²; and the other is hydrogen;

alternatively D¹ and D² join to form —O—CH₂—O—;

R² is hydrogen, C₂₋₆ alkyl substituted with 0-3 R^(2a), a 5-10 memberedheterocyclyl containing 1-4 heteroatoms selected from N, O, and S,substituted with 0-3 R^(2a) where the heterocyclyl is tetrazolyl,pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; and

R^(2a) is OH, C₁₋₄ alkyl, wherein the alkyl is methyl, ethyl, propyl,i-propyl, butyl, and t-butyl, substituted with 0-1 R^(a).

In another embodiment there are provided compounds of formula (II):

or enantiomers, diastereomers, stereoisomers, prodrugs, orpharmaceutically-acceptable salts thereof, wherein

X is CR³ or N;

Y is CR³ or N;

Z is CD¹ or N;

W is CD² or N;

— is an optional bond; provided when the two optional bonds are absent,Z is CHD¹, W is ND² or Z is ND¹ and W is CHD²;

B¹ is hydrogen, halogen, cyano, nitro, —OH, C₁₋₆ alkyl substituted with0-3 R^(1a);

B² is R¹, —C(═O)R¹, —C(═O)OR¹, —C(═O)NR¹¹R¹, —S(═O)₂R¹, —NR¹¹C(═O)R¹,—NR¹¹C(═O)NR¹¹R¹, —NR¹¹C(═O)OR¹, —N(C(═O)OR¹)₂, —NR¹¹S(═O)₂R¹,—N(S(═O)₂R¹)₂, or —NR¹¹R¹;

R¹ is hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(1a), C₁₋₆ haloalkyl,C₂₋₆ alkenyl substituted with 0-3 R^(1a), C₂₋₆ alkynyl substituted with0-3 R^(1a), C₃₋₁₀ cycloalkyl substituted with 0-3 R^(1a), C₆₋₁₀ arylsubstituted with 0-3 R^(1a), a 5-10 membered heterocyclyl containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R^(1a), a5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O,and S, substituted with 0-3 R^(1a);

R^(1a) is hydrogen, ═O, F, Cl, Br, OCF₃, CF₃, CHF₂, CN, NO₂,—(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)₁C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(p)R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substitutedwith 0-2 R^(a), C₁₋₆ haloalkyl, —(CH₂)_(r)-3-14 membered carbocyclesubstituted with 0-1 R^(a), or —(CH₂)_(r)-5-7 membered heterocyclecomprising carbon atoms and 1-4 heteroatoms selected from N, O, andS(O)_(p) substituted with 0-1 R^(a);

D¹ and D² are independently R², halogen, —(C(R¹¹)₂)_(r)R²,—(C(R¹¹)₂)_(r)OR², —C(═O)R², —C(═O)OR², —C(═O)NR¹¹R², —S(═O)₂R²,—S(═O)R², —SR², —NR¹¹C(═O)R², —NR¹¹C(═O)NR¹¹R², —NR¹¹C(═O)OR²,—NR¹¹S(═O)₂R², —NR¹¹R², —C(═O)NR¹¹OR², —OC(═O)OR², —OC(═O)R², orCH═N—OH; alternatively D¹ and D² join to form —O—CH₂—O—;

D³ is hydrogen, halogen, C₁₋₃ alkyl, C₁₋₃ alkoxy, or CN;

R² is hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(2a), C₂₋₆ alkenylsubstituted with 0-3 R^(2a), C₂₋₆ alkynyl substituted with 0-3 R^(2a),C₃₋₁₀ cycloalkyl substituted with 0-3 R^(2a), C₆₋₁₀ aryl substitutedwith 0-3 R^(2a), a 5-10 membered heterocyclyl containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(2a), a 5-10 memberedheteroaryl containing 1-4 heteroatoms selected from N, O, and S,substituted with 0-3 R^(2a);

R^(2a) is hydrogen, ═O, F, Cl, Br, OCF₃, CN, NO₂, —(CH₂)_(r)OR^(b),—(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b), —(CH₂)_(r)C(O)OR^(b),—(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹, —(CH₂)_(r)C(O)NR¹¹R¹¹,—(CH₂)_(r)NR^(b)C(O)R^(c), —(CH₂)_(r)NR^(b)C(O)OR^(c),—NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), —S(O)R^(c),—S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-2 R^(a), C₁₋₆ haloalkyl,—(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a), or—(CH₂)_(r)-5-7 membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p) substituted with 0-2 R^(a);

R¹¹ is independently hydrogen or C₁₋₄ alkyl substituted with 0-1 R^(f),CH₂-phenyl, or —(CH₂)_(r)-5-7 membered heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, O, and S(O)_(p);

alternatively, R¹¹ along with another R¹¹, R¹, or R² on the samenitrogen atom may join to form an optionally substituted azetidinyl,pyrrolidinyl, piperidinyl, morpholinyl, or 4-(C₁₋₆ alkyl)piperazinyl;

R³ is hydrogen or C₁₋₆ alkyl;

R^(a) is hydrogen, F, Cl, Br, OCF₃, CF₃, CHF₂, CN, NO₂,—(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(p)R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substitutedwith 0-1 R^(f), C₁₋₆ haloalkyl, —(CH₂)_(r)-3-14 membered carbocycle, or—(CH₂)_(r)-5-7 membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), alternatively two R^(a) onadjacent or the same carbon atom form a cyclic acetal of the formula—O—(CH₂)_(n)—O—, or —O—CF₂—O—, wherein n is selected from 1 or 2;

R^(b) is hydrogen, C₁₋₆ alkyl substituted with 0-2 R^(d), C₁₋₆haloalkyl, C₃₋₆ cycloalkyl substituted with 0-2 R^(d), or(CH₂)_(r)-phenyl substituted with 0-2 R^(d);

R^(c) is C₁₋₆ alkyl substituted with 0-1 R^(f), C₃₋₆ cycloalkyl, or(CH₂)_(r)-phenyl substituted with 0-1 R^(f);

R^(d) is hydrogen, F, Cl, Br, OCF₃, CF₃, CN, NO₂, —OR^(e),—(CH₂)_(r)C(O)R^(c), —NR^(e)R^(e), —NR^(e)C(O)OR^(c), C₁₋₆ alkyl, or(CH₂)_(r)-phenyl;

R^(e) is hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, or (CH₂)_(r)-phenyl;

R^(f) is hydrogen, halo, NH₂, OH, or OCH₃;

r is 0, 1, 2, 3, or 4; and

p is 0, 1, or 2.

In another embodiment there are provided compounds of formula (II),wherein

D¹ and D² are independently R², —(CH₂)_(r)R², —OR², —C(═O)R², —C(═O)OR²,—C(═O)NR¹¹R², —S(═O)₂R², —S(═O)R², —SR², —NR¹¹C(═O)R², —NR¹¹C(═O)NR¹¹R²,—NR¹¹C(═O)OR², —NR¹¹S(═O)₂R², or —NR¹¹R²;

R² is hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(2a), C₂₋₆ alkenylsubstituted with 0-3 R^(2a), C₃₋₁₀ cycloalkyl substituted with 0-3R^(2a), —C₆₋₁₀ aryl substituted with 0-3 R^(2a), a 5-10 memberedheterocyclyl containing 1-4 heteroatoms selected from N, O, and S,substituted with 0-3 R^(2a), a 5-10 membered heteroaryl containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R^(2a);

R^(2a) is hydrogen, ═O, F, Cl, Br, OCF₃, CF₃, CHF₂, CN, NO₂, OR^(b),SR^(b), —C(O)R^(b), —C(O)OR^(b), —OC(O)R^(b), —NR¹¹R¹¹, —C(O)NR¹¹R¹¹,—NR^(b)C(O)R^(c), —NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹,—S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆alkyl substituted with 0-2 R^(a), —(CH₂)_(r)-3-14 membered carbocyclesubstituted with 0-1 R^(a), wherein the carbocycle is cyclopropyl,cyclobutyl, cyclopentyl or cyclohexyl; or —(CH₂)_(r)-5-7 memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,O, and S(O)_(p) substituted with 0-2 R^(a); and

r is 0, 1, or 2.

In another embodiment there are provided compounds of formula (II),wherein

A is C₆₋₁₀ mono- or bicyclic aryl;

B¹ is hydrogen, halogen, cyano, nitro, —OH, or C₁₋₆ alkyl substitutedwith 0-3 R^(1a);

B² is R¹, —C(═O)R¹, —C(═O)OR¹, —C(═O)NR¹¹R¹, —S(═O)₂R¹, —NR¹¹C(═O)R¹,—NR¹¹C(═O)NR¹¹R¹, —NR¹¹C(═O)OR¹, —N(C(═O)OR¹)₂, —NR¹¹S(═O)₂R¹,—N(S(═O)₂R¹)₂, or —NR¹¹R¹;

R¹ is hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(1a), C₁₋₆ haloalkyl,C₆₋₁₀ aryl substituted with 0-3 R^(1a), a 5-10 membered heterocyclylcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-3 R^(1a), wherein the heterocyclyl is isoquinolin-1(2H)-one,isoindolinyl, isoindoline-1,3-dione, quinolinyl, quinazolinylquinazolin-4(3H)-one, or

and

R^(1a) is hydrogen, ═O, F, Cl, Br, OCF₃, CF₃, CHF₂, CN, NO₂,—(CH₂)_(r)OR^(b).

In another embodiment there are provided compounds of formula (II),wherein

B¹ is C₁₋₄ alkyl or halogen;

B² is R¹, halogen, C₁₋₄ alkyl, —NR¹¹C(═O)R¹, —NR¹¹C(O)OR¹,—NR¹¹C(═O)NR¹¹R¹, or —NR¹¹R¹;

R¹ is hydrogen, C₁₋₄ alkyl, indane or phenyl substituted with 0-3R^(1a), a 5-10 membered heterocyclyl containing 1-4 heteroatoms selectedfrom N, O, and S, substituted with 0-3 R^(1a), a 5-10 memberedheteroaryl containing 1-4 heteroatoms selected from N, O, and S,substituted with 0-3 R^(1a), wherein the heterocyclyl or heteroaryl isselected from

R^(1a) is F, Cl, Br, —NR¹¹R¹¹, —OR^(b), or C₁₋₆ alkyl substituted with0-1 R^(a);

D¹ and D² are independently R², halogen, —OR², —C(═O)R², —C(═O)OR²,—C(═O)NR¹¹R², —NR¹¹C(═O)R², —NR¹¹S(═O)₂R², —SR², S(═O)R², S(═O)₂R², or—NR¹¹R²; alternatively D¹ and D² join to form —O—CH₂—O—;

R² is hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(2a), a 5-10 memberedheterocyclyl containing 1-4 heteroatoms selected from N, O, and S,substituted with 0-3 R^(2a), wherein the heterocyclyl is selected frompyrimidinyl, morpholinyl, piperidinyl, pyrrolidinyl, pyridinyl,tetrahydropyranyl, or tetrahydrofuranyl;

R^(2a) is hydrogen, CN, C₁₋₆ alkyl, —N(CH₃)₂ or —OR^(b);

R¹¹ is independently hydrogen or C₁₋₄ alkyl, or CH₂-phenyl;

R^(a) is hydrogen, F, Cl, Br, OCF₃, CF₃, CHF₂, CN, NO₂, —OR^(b),—SR^(b), —C(O)R^(b), —C(O)OR^(b), —OC(O)R^(b), —NR¹¹R¹¹, —C(O)NR¹¹R¹¹,—NR^(b)C(O)R^(c), —NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹,—S(O)_(p)NR¹¹R¹¹, NR^(b)S(O)_(p)R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆alkyl substituted with 0-1 R^(f), C₁₋₆ haloalkyl, —(CH₂)_(r)-3-6membered carbocycle, or —(CH₂)_(r)-5-7 membered heterocycle comprisingcarbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p),wherein the heterocycle is pyrrolidinyl, pyrrolyl, pyrazolyl,imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furyl,thienyl, pyridyl, pyrazinyl, pyrimidinyl, morpholinyl, thiamorpholinyl,triazolyl, indolyl, benzothiazolyl, benzoxazolyl, benzothienyl,quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, benzimidazolyl,benzopyranyl, benzofuryl, benzisothiazolyl, benzisoxazolyl,benzodiazinyl, or benzofurazanyl;

R^(b) is hydrogen, C₁₋₄ alkyl substituted with 0-2 R^(d), C₁₋₄haloalkyl, C₃₋₆ cycloalkyl substituted with 0-2 R^(d), or(CH₂)_(r)-phenyl substituted with 0-2 R^(d);

R^(c) is C₁₋₄ alkyl substituted with 0-1 R^(f), C₃₋₆ cycloalkyl, or(CH₂)_(r)-phenyl substituted with 0-1 R^(f);

R^(d) is hydrogen, F, Cl, Br, OCF₃, CF₃, CN, NO₂, —OR^(e), —C(O)R^(c),—NR^(e)R^(e), —NR^(e)C(O)OR^(c), C₁₋₆ alkyl, or (CH₂)_(r)-phenyl;

R^(e) is hydrogen, C₁₋₄alkyl, C₃₋₆ cycloalkyl, or (CH₂)_(r)-phenyl;

R^(f) is hydrogen, halo, or NH₂; and

r is 0 or 1.

In another embodiment there are provided compounds according to formula(IIa), (IIb), or (IIc):

In another embodiment there are provided compounds according to formula(IId) or (IIe):

In another embodiment there are provided compounds according to formula(IIf) or (IIg):

In another embodiment there are provided compounds of formulae(IIa)-(IIg), wherein

B¹ is methyl or fluorine;

B² is hydrogen, R^(1b), —NR¹¹C(═O)R^(1c), —NR¹¹C(═O)NR¹¹R^(1d), or—NR¹¹R^(1e);

R^(1b) is,

any of which are substituted with 0-3 R^(1a);

R^(1c) is C₁₋₆ alkyl,

any of which are substituted with 0-2 R^(a);

R^(1d) is phenyl substituted with 0-1 R^(1a);

R^(1e) is quinazolinyl substituted with 0-1 R^(1a);

R^(1a) is selected from hydrogen, F, Cl, CN, methyl, ethyl, CF₃, OH, andO-methyl;

D¹ and D² are independently R², F, Cl, Br, —OR², —C(═O)R², —C(═O)OR²,—C(═O)NR¹¹R², —S(═O)₂R², —S(═O)R², —SR², —NR¹¹C(═O)R², —NR¹¹S(═O)₂R²,and —NR¹¹R²;

R² is hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(2a), piperazinyl,pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl,piperidinyl, pyridinyl, imidazolyl, pyrazinyl, or pyrimidinyl, any ofwhich are substituted with 0-3 R^(2a);

R^(2a) is hydrogen, CN, —OR^(b), or morpholinyl;

R¹¹ is hydrogen or C₁₋₄ alkyl;

R^(a) is hydrogen, F, Cl, C₁₋₄ alkyl, —OR^(b), —NR¹¹R¹¹ imidazolyl, ormorpholinyl; and

R^(b) is hydrogen or C₁₋₆ alkyl.

Where the specification refers to compounds of formula (I), it isintended to include compounds of formulae (Ia)-(Ig), (II), (IIa)-(IIg),either individually or in any combination.

In another embodiment there is provided a compound of formula (I),wherein

D¹ and D² are independently R², halogen, —OR², —C(═O)R², —C(═O)NR¹¹R²,—NR¹¹C(═O)R², —NR¹¹S(═O)₂R², or —NR¹¹R²;

R² is hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(2a), a 5-10 memberedheterocyclyl containing 1-4 heteroatoms selected from N, O, and S,substituted with 0-3 R^(2a), wherein the heterocyclyl is selected frompyrimidinyl, morpholinyl, pyrrolidinyl, pyridinyl, tetrahydropyranyl, ortetrahydrofuranyl; and

R^(2b) is C₁₋₆ alkyl substituted with 0-3 R^(2a), a 5-10 memberedheterocyclyl containing 1-4 heteroatoms selected from N, O, and S,substituted with 0-3 R^(2a), wherein the heterocyclyl is selected frompyrimidinyl, morpholinyl, pyrrolidinyl, pyridinyl, tetrahydropyranyl, ortetrahydrofuranyl.

In another embodiment there is provided a compound of formula (I),wherein A is C₆₋₁₀ mono- or bicyclic aryl substituted with 0-3 B.

In another embodiment there is provided a compound of formula (I),wherein A is phenyl substituted with 0-2 B.

In another embodiment there is provided a compound of formula (I),wherein B is R¹, halogen, cyano, nitro, —OR¹, —C(═O)R¹, —C(═O)OR¹,—C(═O)NR¹¹R¹, —S(═O)₂R¹, —NR¹¹C(═O)R¹, —NR¹¹C(═O)NR¹¹R¹, —NR¹¹S(═O)₂R¹,—N(S(═O)₂R¹)₂, or —NR¹¹R¹.

In another embodiment there is provided a compound of formula (I),wherein B is R¹, halogen, —C(═O)OR¹, —S(═O)₂R¹, —NR¹¹C(═O)R¹,—NR¹¹C(═O)NR¹¹R¹, —NR¹¹S(═O)₂R¹, N(S(═O)₂R¹)₂, or —NR¹¹R¹.

In another embodiment there is provided a compound of formula (I) or(II), wherein R¹ is hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(1a),C₁₋₆ haloalkyl, C₆₋₁₀ aryl substituted with 0-3 R^(1a), a 5-10 memberedheterocyclyl containing 1-4 heteroatoms selected from N, O, and S,substituted with 0-3 R^(1a), a 5-10 membered heteroaryl containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R^(1a).

In another embodiment there is provided a compound of formula (I) or(II), wherein R¹ is hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(1a),C₁₋₆ haloalkyl, C₆₋₁₀ aryl substituted with 0-3 R^(1a), a 5-10 memberedheterocyclyl containing 1-4 heteroatoms selected from N, O, and S,substituted with 0-3 R^(1a), wherein the heterocyclyl isisoquinolin-1(2H)-one, isoindolinyl, isoindoline-1,3-dione, quinolinyl,quinazolinyl quinazolin-4(3H)-one or pyrido[3,2-d]pyrimidine.

In another embodiment there is provided a compound of formula (I) or(II), wherein R¹ is hydrogen, trifluoromethyl, C₁₋₄ alkyl substitutedwith 0-1 R^(1a), phenyl substituted with 0-3 R^(1a), a 5-10 memberedheteroaryl containing 1-4 heteroatoms selected from N, O, and S,substituted with 0-3 R^(1a), wherein the heteroaryl ispyrido[3,2-d]pyrimidine.

In another embodiment there is provided a compound of formula (I) or(II), wherein R¹ is hydrogen, methyl, phenyl substituted with 0-3R^(1a), a 5-10 membered heterocyclyl containing 1-4 heteroatoms selectedfrom N, O, and S, substituted with 0-3 R^(1a), a 5-10 memberedheteroaryl containing 1-4 heteroatoms selected from N, O, and S,substituted with 0-3 R^(1a), wherein the heterocycle is selected frompyridinyl, benzimidazolyl,

In another embodiment there is provided a compound of formula (I) or(II), wherein R^(1a) is F, Cl, Br, —NR¹¹R¹¹, C₁₋₆, alkyl substitutedwith 0-1 R^(a), or —OR^(b).

In another embodiment there is provided a compound of formula (I) or(II), wherein R² is hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(2a),C₂₋₆ alkenyl substituted with 0-3 R^(2a), C₃₋₁₀ cycloalkyl substitutedwith 0-3 R^(2a), C₆₋₁₀ aryl substituted with 0-3 R^(2a), a 5-10 memberedheterocyclyl containing 1-4 heteroatoms selected from N, O, and S,substituted with 0-3 R^(2a), a 5-10 membered heteroaryl containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R^(2a).

R² is hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(2a), ethenyl, C₃₋₁₀cycloalkyl substituted with 0-3 R^(2a), C₆₋₁₀ aryl substituted with 0-3R^(2a), a 5-10 membered heterocyclyl containing 1-4 heteroatoms selectedfrom N, O, and S, substituted with 0-3 R^(2a), wherein the heterocyclylis pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl,tetrahydrofuranyl, tetrahydropyranyl; a 5-10 membered heteroarylcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-3 R^(2a), wherein the heteroaryl is pyrimidinyl, imidazolyl,pyrazinyl, thiadiazolyl, pyridinyl, quinolinyl, isoquinolinyl, orthiazolyl.

In another embodiment there is provided a compound of formula (I) or(II), wherein R² is hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(2a), a5-10 membered heterocyclyl containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(2a) where the heterocyclyl istetrazolyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

In another embodiment there is provided a compound of formula (I) or(II), wherein R² is hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(2a),C₃₋₁₀ cyclopropyl substituted with 0-3 R^(2a), a 5-10 memberedheterocyclyl containing 1-4 heteroatoms selected from N, O, and S,substituted with 0-3 R^(2a), wherein the heterocyclyl is selected frompiperazinyl, pyrrolidinyl, tetrahydrofuranyl, morpholinyl, dioxolanyl,piperidinyl, a 5-10 membered heteroaryl containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(2a), wherein theheteroaryl is selected from pyridinyl, imidazolyl, pyrazinyl,pyrimidinyl, tetrazolyl, thiadiazolyl.

In another embodiment there is provided a compound of formula (I),wherein R² is C₁₋₄alkyl substituted with OH, preferably R² beinghydroxypropane.

In another embodiment there is provided a compound of formula (I) or(II), wherein R^(2a) is hydrogen, ═O, F, Cl, Br, OCF₃, CF₃, CHF₂, CN,NO₂, OR^(b), SR^(b), —C(O)R^(b), —C(O)OR^(b), —OC(O)R^(b), —NR¹¹R¹¹,—C(O)NR¹¹R¹¹, —NR^(b)C(O)R^(c), —NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹,—S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆alkyl substituted with 0-2 R^(a), —(CH₂)_(r)-3-14 membered carbocyclesubstituted with 0-1 R^(a), wherein the carbocycle is cyclopropyl,cyclobutyl, cyclopentyl or cyclohexyl; or —(CH₂)_(r)-5-7 memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,O, and S(O)_(p) substituted with 0-2 R^(a).

In another embodiment there is provided a compound of formula (I) or(II), wherein R^(2a) is hydrogen, —(CH₂)_(r)OR^(b),—(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹, —NR^(b)C(O)NR¹¹R¹¹,—NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-2 R^(a), or—(CH₂)_(r)-5-7 membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p) substituted with 0-2 R^(a),wherein the heterocycle is selected from pyridinyl, pyrrolidinyl,pyrrolidinonyl, morpholinyl, imidazolyl, piperidinyl.

In another embodiment there is provided a compound of formula (I) or(II), wherein R^(a) is hydrogen, F, Cl, Br, OCF₃, CF₃, CHF₂, CN, NO₂,—OR^(b), —SR^(b), —C(O)R^(b), C(O)OR^(b), —OC(O)R^(b), —NR¹¹R¹¹,—C(O)NR¹¹R¹¹, —NR^(b)C(O)R^(c), —NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹,—S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆alkyl substituted with 0-1 R^(f), C₁₋₆ haloalkyl, —(CH₂)_(r)-3-6membered carbocycle, or —(CH₂)_(r)-5-7 membered heterocycle comprisingcarbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p),wherein the heterocycle is pyrrolidinyl, pyrrolyl, pyrazolyl,imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furyl,thienyl, pyridyl, pyrazinyl, pyrimidinyl, morpholinyl, thiamorpholinyl,triazolyl, indolyl, benzothiazolyl, benzoxazolyl, benzothienyl,quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, benzimidazolyl,benzopyranyl, benzofuryl, benzisothiazolyl, benzisoxazolyl,benzodiazinyl, or benzofurazanyl.

In another embodiment there is provided a compound of formula (I) or(II), wherein R^(a) is hydrogen, F, Cl, Br, OCF₃, CF₃, CHF₂, CN, NO₂,—OR^(b), —SR^(b), —C(O)R^(b), —C(O)OR^(b), —OC(O)R^(b), —NR¹¹R¹¹,—C(O)NR¹¹R¹¹, —NR^(b)C(O)R^(c), —NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹,—S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆alkyl, C₁₋₆ haloalkyl, —(CH₂)_(r)-3-6 membered carbocycle phenyl, or—(CH₂)_(r)-5-7 membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein the heterocycle isthiazolyl, pyridinyl, piperidinyl, morpholinyl, piperazinyl,pyrrolidinyl, pyrrolidin-one,

In another embodiment there is provided a compound of formula (I) or(II), wherein R^(b) is hydrogen, C₁₋₆ alkyl substituted with 0-2 R^(d),C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl substituted with 0-2 R^(d), or(CH₂)_(r)-phenyl substituted with 0-2 R^(d).

In another embodiment there is provided a compound of formula (I) or(II), wherein R^(c) is C₁₋₆ alkyl substituted with 0-1 R^(f), C₃₋₆cycloalkyl, or (CH₂)_(r)-phenyl substituted with 0-1 R^(f).

In another embodiment there is provided a compound of formula (I) or(II), wherein R^(d) is hydrogen, F, Cl, Br, OCF₃, CF₃, CN, NO₂, —OR^(c),—C(O)R^(c), —NR^(e)R^(e), —NR^(e)C(O)OR^(c), C₁₋₆ alkyl, or(CH₂)_(r)-phenyl.

In another embodiment there is provided a compound of formula (I) or(II), wherein R^(e) is hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, or(CH₂)_(r)-phenyl.

In another embodiment there is provided a compound of formula (I) or(II), wherein R^(f) is hydrogen, halo, or NH₂.

In another embodiment, there is provided a pharmaceutical compositioncomprising one or more compounds of formula (I) or (II) and apharmaceutically acceptable carrier or diluent.

The present invention is also directed to pharmaceutical compositionsuseful in treating diseases associated with kinase modulation, includingmodulation (especially inhibition) of Btk and other Tec family kinasessuch as Itk, comprising compounds of formula (I) or (II), orpharmaceutically-acceptable salts thereof, andpharmaceutically-acceptable carriers or diluents.

The invention further relates to methods of treating diseases associatedwith the kinase modulation, including the modulation of Btk and otherTec family kinases such as Itk, comprising administering to a patient inneed of such treatment a therapeutically-effective amount of a compoundaccording to formula (I) or (II).

The present invention also provides processes and intermediates formaking the compounds of the present invention or stereoisomers,tautomers, pharmaceutically acceptable salts, solvates, or prodrugsthereof.

The present invention also provides a method for treating proliferativediseases, allergic diseases, autoimmune diseases and inflammatorydiseases, comprising administering to a host in need of such treatment atherapeutically effective amount of at least one of the compounds of thepresent invention or stereoisomers, tautomers, pharmaceuticallyacceptable salts, solvates, or prodrugs thereof.

The present invention also provides a method for treating a disease,comprising administering to a patient in need of such treatment atherapeutically-effective amount of a compound of formula (I) or (II),wherein the disease is systemic lupus erythematosus (SLE), rheumatoidarthritis, multiple sclerosis (MS), or transplant rejection.

The present invention also provides a method of treating a conditionassociated with a proliferative disease, an allergic disease, anautoimmune disease or an inflammatory disease, comprising administeringto a patient in need of such treatment a therapeutically-effectiveamount of a compound of formula (I) or (II).

The present invention also provides a method of treating a conditioncomprising administering to a patient in need of such treatment atherapeutically-effective amount of a compound of formula (I) or (II),wherein the condition is selected from acute myelogenous leukemia,chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma,multiple myeloma, solid tumors, ocular neovasculization, and infantilehaemangiomas, B cell lymphoma, systemic lupus erythematosus (SLE),rheumatoid arthritis, psoriatic arthritis, multiple vasculitides,idiopathic thrombocytopenic purpura (ITP), myasthenia gravis, allergicrhinitis, multiple sclerosis (MS), transplant rejection, Type Idiabetes, membranous nephritis, inflammatory bowel disease, autoimmunehemolytic anemia, autoimmune thyroiditis, cold and warm agglutinindiseases, Evan's syndrome, hemolytic uremic syndrome/thromboticthrombocytopenic purpura (HUS/TTP), sarcoidosis, Sjögren's syndrome,peripheral neuropathies, pemphigus vulgaris and asthma.

The present invention also provides a method for treating rheumatoidarthritis, comprising administering to a patient in need of suchtreatment a therapeutically-effective amount of a compound of formula(I) or (II).

The present invention also provides a method of treating a B-cellmediated disease, comprising administering to a patient in need of suchtreatment a therapeutically-effective amount of a compound of formula(I) or (II).

The present invention also provides a method of treating a B-cellmediated disease, comprising administering to a patient in need of suchtreatment a therapeutically-effective amount of a compound of formula(I) or (II), wherein the B-cell mediated disease is a disease modulatedby a kinase selected from Btk, Bmx, Itk, Txk and Tec.

The present invention also provides a method of treating diseases,comprising administering to a patient in need of such treatment atherapeutically-effective amount of a compound of formula (I) or (II),or pharmaceutically acceptable salt thereof, in combination with othertherapeutic agents.

The present invention also provides the compounds of the presentinvention or stereoisomers, tautomers, pharmaceutically acceptablesalts, solvates, or prodrugs thereof, for use in therapy.

In another embodiment, compounds of formula (I) or (II), are selectedfrom exemplified examples or combinations of exemplified examples orother embodiments herein.

In another embodiment, the IC₅₀ value of compounds of formula (I) or(II) in the Btk assay described below is <10 μM.

In another embodiment, the IC₅₀ value of compounds of formula (I) or(II) in the Btk assay described below is <1 μM.

In another embodiment, the IC₅₀ value of compounds of formula (I) or(II) in the Btk assay described below is <0.01 μM.

The present invention also provides the use of the compounds of thepresent invention or stereoisomers, tautomers, pharmaceuticallyacceptable salts, solvates, or prodrugs thereof, for the manufacture ofa medicament for the treatment of cancers, an allergic disease, anautoimmune disease or an inflammatory disease.

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. Thisinvention encompasses all combinations of preferred aspects and/orembodiments of the invention noted herein. It is understood that any andall embodiments of the present invention may be taken in conjunctionwith any other embodiment or embodiments to describe additionalembodiments. It is also to be understood that each individual element ofthe embodiments is its own independent embodiment. Furthermore, anyelement of an embodiment is meant to be combined with any and all otherelements from any embodiment to describe an additional embodiment.

DETAILED DESCRIPTION OF THE INVENTION

The following are definitions of terms used in this specification andappended claims. The initial definition provided for a group or termherein applies to that group or term throughout the specification andclaims, individually or as part of another group, unless otherwiseindicated.

When any variable (e.g., R³) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 0-2 R³, then saidgroup may optionally be substituted with up to two R³ groups and R³ ateach occurrence is selected independently from the definition of R³.Also, combinations of substituents and/or variables are permissible onlyif such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

In cases wherein there are nitrogen atoms (e.g., amines) on compounds ofthe present invention, these can be converted to N-oxides by treatmentwith an oxidizing agent (e.g., MCPBA and/or hydrogen peroxides) toafford other compounds of this invention. Thus, all shown and claimednitrogen atoms are considered to cover both the shown nitrogen and itsN-oxide (N→O) derivative.

In accordance with a convention used in the art,

is used in structural formulas herein to depict the bond that is thepoint of attachment of the moiety or substituent to the core or backbonestructure.

A dash “-” that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —CONH₂ isattached through the carbon atom.

The term “optionally substituted” in reference to a particular moiety ofthe compound of Formula (I) (e.g., an optionally substituted heteroarylgroup) refers to a moiety having 0, 1, 2, or more substituents. Forexample, “optionally substituted alkyl” encompasses both “alkyl” and“substituted alkyl” as defined below. It will be understood by thoseskilled in the art, with respect to any group containing one or moresubstituents, that such groups are not intended to introduce anysubstitution or substitution patterns that are sterically impractical,synthetically non-feasible and/or inherently unstable.

As used herein, the term “at least one chemical entity” isinterchangeable with the term “a compound.”

As used herein, the term “alkyl” or “alkylene” is intended to includeboth branched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms. For example, “C₁₋₁₀ alkyl”(or alkylene), is intended to include C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈,C₉, and C₁₀ alkyl groups. Additionally, for example, “C₁-C₆ alkyl”denotes alkyl having 1 to 6 carbon atoms. Alkyl groups can beunsubstituted or substituted so that one or more of its hydrogens arereplaced by another chemical group. Example alkyl groups include, butare not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl andisopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g.,n-pentyl, isopentyl, neopentyl), and the like.

Alkenyl” or “alkenylene” is intended to include hydrocarbon chains ofeither straight or branched configuration and having one or more doublecarbon-carbon bonds that may occur in any stable point along the chain.For example, “C₂₋₆ alkenyl” (or alkenylene), is intended to include C₂,C₃, C₄, C₅, and C₆ alkenyl groups. Examples of alkenyl include, but arenot limited to, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl,2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl,5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, and the like.

“Alkynyl” or “alkynylene” is intended to include hydrocarbon chains ofeither straight or branched configuration and having one or more triplecarbon-carbon bonds that may occur in any stable point along the chain.For example, “C₂₋₆ alkynyl” (or alkynylene), is intended to include C₂,C₃, C₄, C₅, and C₆ alkynyl groups; such as ethynyl, propynyl, butynyl,pentynyl, hexynyl and the like.

One skilled in the field will understand that, when the designation“CO₂” is used herein, this is intended to refer to the group

When the term “alkyl” is used together with another group, such as in“arylalkyl”, this conjunction defines with more specificity at least oneof the substituents that the substituted alkyl will contain. Forexample, “arylalkyl” refers to a substituted alkyl group as definedabove where at least one of the substituents is an aryl, such as benzyl.Thus, the term aryl(C₀₋₄)alkyl includes a substituted lower alkyl havingat least one aryl substituent and also includes an aryl directly bondedto another group, i.e., aryl(C₀)alkyl. The term “heteroarylalkyl” refersto a substituted alkyl group as defined above where at least one of thesubstituents is a heteroaryl.

When reference is made to a substituted alkenyl, alkynyl, alkylene,alkenylene, or alkynylene group, these groups are substituted with oneto three substituents as defined above for substituted alkyl groups.

The term “alkoxy” refers to an oxygen atom substituted by alkyl orsubstituted alkyl, as defined herein. For example, the term “alkoxy”includes the group —O—C₁₋₆alkyl such as methoxy, ethoxy, propoxy,isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyloxy,isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy, andthe like. “Lower alkoxy” refers to alkoxy groups having one to fourcarbons.

It should be understood that the selections for all groups, includingfor example, alkoxy, thioalkyl, and aminoalkyl, will be made by oneskilled in the field to provide stable compounds.

The term “substituted”, as used herein, means that any one or morehydrogens on the designated atom or group is replaced with a selectionfrom the indicated group, provided that the designated atom's normalvalence is not exceeded. When a substituent is oxo, or keto, (i.e., ═O)then 2 hydrogens on the atom are replaced. Keto substituents are notpresent on aromatic moieties. Unless otherwise specified, substituentsare named into the core structure. For example, it is to be understoodthat when (cycloalkyl)alkyl is listed as a possible substituent, thepoint of attachment of this substituent to the core structure is in thealkyl portion. Ring double bonds, as used herein, are double bonds thatare formed between two adjacent ring atoms (e.g., C═C, C═N, or N═N).

Combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds or useful syntheticintermediates. A stable compound or stable structure is meant to imply acompound that is sufficiently robust to survive isolation from areaction mixture to a useful degree of purity, and subsequentformulation into an efficacious therapeutic agent. It is preferred thatthe presently recited compounds do not contain a N-halo, S(O)₂H, orS(O)H group.

The term “cycloalkyl” refers to cyclized alkyl groups, including mono-,bi- or poly-cyclic ring systems. C₃₋₇ cycloalkyl is intended to includeC₃, C₄, C₅, C₆, and C₇ cycloalkyl groups. Example cycloalkyl groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, norbornyl, and the like. As used herein, “carbocycle” or“carbocyclic residue” is intended to mean any stable 3-, 4-, 5-, 6-, or7-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, or13-membered bicyclic or tricyclic ring, any of which may be saturated,partially unsaturated, unsaturated or aromatic. Examples of suchcarbocycles include, but are not limited to, cyclopropyl, cyclobutyl,cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl,cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl,cyclooctadienyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane,[4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl,indanyl, adamantyl, anthracenyl, and tetrahydronaphthyl (tetralin). Asshown above, bridged rings are also included in the definition ofcarbocycle (e.g., [2.2.2]bicyclooctane). Preferred carbocycles, unlessotherwise specified, are cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, and phenyl. When the term “carbocycle” is used, it isintended to include “aryl”. A bridged ring occurs when one or morecarbon atoms link two non-adjacent carbon atoms. Preferred bridges areone or two carbon atoms. It is noted that a bridge always converts amonocyclic ring into a bicyclic ring. When a ring is bridged, thesubstituents recited for the ring may also be present on the bridge.

The term “aryl” refers to monocyclic or bicyclic aromatic hydrocarbongroups having 6 to 12 carbon atoms in the ring portion, such as phenyl,and naphthyl groups, each of which may be substituted.

Accordingly, in compounds of formula (I), the term “cycloalkyl” includescyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,bicyclooctyl, etc., as well as the following ring systems,

and the like, which optionally may be substituted at any available atomsof the ring(s). Preferred cycloalkyl groups include cyclopropyl,cyclopentyl, cyclohexyl, and

The term “halo” or “halogen” refers to chloro, bromo, fluoro and iodo.

The term “haloalkyl” means a substituted alkyl having one or more halosubstituents. For example, “haloalkyl” includes mono, bi, andtrifluoromethyl.

The term “haloalkoxy” means an alkoxy group having one or more halosubstituents. For example, “haloalkoxy” includes OCF₃.

Thus, examples of aryl groups include:

(fluorenyl) and the like, which optionally may be substituted at anyavailable carbon or nitrogen atom. A preferred aryl group isoptionally-substituted phenyl.

The terms “heterocycloalkyl”, “heterocyclo”, “heterocyclic”, or“heterocyclyl” may be used interchangeably and refer to substituted andunsubstituted non-aromatic 3- to 7-membered monocyclic groups, 7- to11-membered bicyclic groups, and 10- to 15-membered tricyclic groups, inwhich at least one of the rings has at least one heteroatom (O, S or N),said heteroatom containing ring preferably having 1, 2, or 3 heteroatomsselected from O, S, and N. Each ring of such a group containing aheteroatom can contain one or two oxygen or sulfur atoms and/or from oneto four nitrogen atoms provided that the total number of heteroatoms ineach ring is four or less, and further provided that the ring containsat least one carbon atom. The nitrogen and sulfur atoms may optionallybe oxidized and the nitrogen atoms may optionally be quaternized. Thefused rings completing the bicyclic and tricyclic groups may containonly carbon atoms and may be saturated, partially saturated, orunsaturated. The heterocyclo group may be attached at any availablenitrogen or carbon atom. The term “heterocycle” includes “heteroaryl”groups. As valence allows, if said further ring is cycloalkyl orheterocyclo it is additionally optionally substituted with ═O (oxo).

Exemplary monocyclic heterocyclyl groups include azetidinyl,pyrrolidinyl, oxetanyl, imidazolinyl, oxazolidinyl, isoxazolinyl,thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidyl,piperazinyl, 2-oxopiperazinyl, 2-oxopiperidyl, 2-oxopyrrolodinyl,2-oxoazepinyl, azepinyl, 1-pyridonyl, 4-piperidonyl, tetrahydropyranyl,morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinylsulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl and the like.Exemplary bicyclic heterocyclo groups include quinuclidinyl. Additionalheterocyclyl groups include

The term “heteroaryl” refers to substituted and unsubstituted aromatic5- or 6-membered monocyclic groups, 9- or 10-membered bicyclic groups,and 11- to 14-membered tricyclic groups which have at least oneheteroatom (O, S or N) in at least one of the rings, saidheteroatom-containing ring preferably having 1, 2, or 3 heteroatomsselected from O, S, and N. Each ring of the heteroaryl group containinga heteroatom can contain one or two oxygen or sulfur atoms and/or fromone to four nitrogen atoms provided that the total number of heteroatomsin each ring is four or less and each ring has at least one carbon atom.The fused rings completing the bicyclic and tricyclic groups may containonly carbon atoms and may be saturated, partially saturated, orunsaturated. The nitrogen and sulfur atoms may optionally be oxidizedand the nitrogen atoms may optionally be quaternized. Heteroaryl groupswhich are bicyclic or tricyclic must include at least one fully aromaticring but the other fused ring or rings may be aromatic or non-aromatic.The heteroaryl group may be attached at any available nitrogen or carbonatom of any ring. As valence allows, if said further ring is cycloalkylor heterocyclo it is additionally optionally substituted with ═O (oxo).

Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl,pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl,isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, triazinyl and the like.

Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl,benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl,tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl,indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl,cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridyl,dihydroisoindolyl, tetrahydroquinolinyl, and the like.

Exemplary tricyclic heteroaryl groups include carbazolyl, benzindolyl,phenanthrollinyl, acridinyl, phenanthridinyl, xanthenyl and the like.

In compounds of formula (I), preferred heteroaryl groups include

and the like, which optionally may be substituted at any availablecarbon or nitrogen atom.

Unless otherwise indicated, when reference is made to aspecifically-named aryl (e.g., phenyl), cycloalkyl (e.g., cyclohexyl),heterocyclo (e.g., pyrrolidinyl, piperidinyl, and morpholinyl) orheteroaryl (e.g., tetrazolyl, imidazolyl, pyrazolyl, triazolyl,thiazolyl, and furyl) the reference is intended to include rings having0 to 3, preferably 0-2, substituents selected from those recited abovefor the aryl, cycloalkyl, heterocyclo and/or heteroaryl groups, asappropriate.

The term “carbocyclyl” or “carbocyclic” refers to a saturated orunsaturated monocyclic or bicyclic ring in which all atoms of all ringsare carbon. Thus, the term includes cycloalkyl and aryl rings.Monocyclic carbocycles have 3 to 6 ring atoms, still more typically 5 or6 ring atoms. Bicyclic carbocycles have 7 to 12 ring atoms, e.g.,arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10ring atoms arranged as a bicyclo [5,6] or [6,6] system. Examples ofmono- and bicyclic carbocycles include cyclopropyl, cyclobutyl,cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl,cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl,phenyl and naphthyl. The carbocyclic ring may be substituted in whichcase the substituents are selected from those recited above forcycloalkyl and aryl groups.

The term “heteroatoms” shall include oxygen, sulfur and nitrogen.

When the term “unsaturated” is used herein to refer to a ring or group,the ring or group may be fully unsaturated or partially unsaturated.

Throughout the specification, groups and substituents thereof may bechosen by one skilled in the field to provide stable moieties andcompounds and compounds useful as pharmaceutically-acceptable compoundsand/or intermediate compounds useful in makingpharmaceutically-acceptable compounds.

The compounds of formula (I) may exist in a free form (with noionization) or can form salts which are also within the scope of thisinvention. Unless otherwise indicated, reference to an inventivecompound is understood to include reference to the free form and tosalts thereof. The term “salt(s)” denotes acidic and/or basic saltsformed with inorganic and/or organic acids and bases. In addition, theterm “salt(s) may include zwitterions (inner salts), e.g., when acompound of formula (I), contains both a basic moiety, such as an amineor a pyridine or imidazole ring, and an acidic moiety, such as acarboxylic acid. Pharmaceutically acceptable (i.e., non-toxic,physiologically acceptable) salts are preferred, such as, for example,acceptable metal and amine salts in which the cation does not contributesignificantly to the toxicity or biological activity of the salt.However, other salts may be useful, e.g., in isolation or purificationsteps which may be employed during preparation, and thus, arecontemplated within the scope of the invention. Salts of the compoundsof the formula (I) may be formed, for example, by reacting a compound ofthe formula (I) with an amount of acid or base, such as an equivalentamount, in a medium such as one in which the salt precipitates or in anaqueous medium followed by lyophilization.

Exemplary acid addition salts include acetates (such as those formedwith acetic acid or trihaloacetic acid, for example, trifluoroaceticacid), adipates, alginates, ascorbates, aspartates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, cyclopentanepropionates, digluconates,dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates,glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides(formed with hydrochloric acid), hydrobromides (formed with hydrogenbromide), hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates(formed with maleic acid), methanesulfonates (formed withmethanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates,oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates,picrates, pivalates, propionates, salicylates, succinates, sulfates(such as those formed with sulfuric acid), sulfonates (such as thosementioned herein), tartrates, thiocyanates, toluenesulfonates such astosylates, undecanoates, and the like.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts; alkaline earth metal salts such ascalcium and magnesium salts; barium, zinc, and aluminum salts; saltswith organic bases (for example, organic amines) such as trialkylaminessuch as triethylamine, procaine, dibenzylamine,N-benzyl-β-phenethylamine, 1-ephenamine, N,N′-dibenzylethylene-diamine,dehydroabietylamine, N-ethylpiperidine, benzylamine, dicyclohexylamineor similar pharmaceutically acceptable amines and salts with amino acidssuch as arginine, lysine and the like. Basic nitrogen-containing groupsmay be quaternized with agents such as lower alkyl halides (e.g.,methyl, ethyl, propyl, and butyl chlorides, bromides and iodides),dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamylsulfates), long chain halides (e.g., decyl, lauryl, myristyl and stearylchlorides, bromides and iodides), aralkyl halides (e.g., benzyl andphenethyl bromides), and others. Preferred salts includemonohydrochloride, hydrogensulfate, methanesulfonate, phosphate ornitrate salts.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic groups such as amines; and alkali or organic saltsof acidic groups such as carboxylic acids. The pharmaceuticallyacceptable salts include the conventional non-toxic salts or thequaternary ammonium salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. For example, suchconventional non-toxic salts include those derived from inorganic acidssuch as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, andnitric; and the salts prepared from organic acids such as acetic,propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric,ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, andisethionic, and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 18th Edition, Mack Publishing Company, Easton,Pa. (1990), the disclosure of which is hereby incorporated by reference.

All stereoisomers of the compounds of the instant invention arecontemplated, either in admixture or in pure or substantially pure form.Stereoisomers may include compounds which are optical isomers throughpossession of one or more chiral atoms, as well as compounds which areoptical isomers by virtue of limited rotation about one or more bonds(atropisomers). The definition of compounds according to the inventionembraces all the possible stereoisomers and their mixtures. It veryparticularly embraces the racemic forms and the isolated optical isomershaving the specified activity. The racemic forms can be resolved byphysical methods, such as, for example, fractional crystallization,separation or crystallization of diastereomeric derivatives orseparation by chiral column chromatography. The individual opticalisomers can be obtained from the racemates from the conventionalmethods, such as, for example, salt formation with an optically activeacid followed by crystallization.

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include deuteriumand tritium. Isotopes of carbon include ¹³C and ¹⁴C.Isotopically-labeled compounds of the invention can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described herein, using an appropriateisotopically-labeled reagent in place of the non-labeled reagentotherwise employed.

Prodrugs and solvates of the inventive compounds are also contemplated.The term “prodrug” denotes a compound which, upon administration to asubject, undergoes chemical conversion by metabolic or chemicalprocesses to yield a compound of the formula (I), and/or a salt and/orsolvate thereof. Any compound that will be converted in vivo to providethe bioactive agent (i.e., the compound for formula (I)) is a prodrugwithin the scope and spirit of the invention. For example, compoundscontaining a carboxy group can form physiologically hydrolyzable esterswhich serve as prodrugs by being hydrolyzed in the body to yield formula(I) compounds per se. Such prodrugs are preferably administered orallysince hydrolysis in many instances occurs principally under theinfluence of the digestive enzymes. Parenteral administration may beused where the ester per se is active, or in those instances wherehydrolysis occurs in the blood. Examples of physiologically hydrolyzableesters of compounds of formula (I) include C₁₋₆alkylbenzyl,4-methoxybenzyl, indanyl, phthalyl, methoxymethyl,C₁₋₆alkanoyloxy-C₁₋₆alkyl, e.g., acetoxymethyl, pivaloyloxymethyl orpropionyloxymethyl, C₁₋₆alkoxycarbonyloxy-C₁₋₆alkyl, e.g.,methoxycarbonyl-oxymethyl or ethoxycarbonyloxymethyl, glycyloxymethyl,phenylglycyloxymethyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl andother well known physiologically hydrolyzable esters used, for example,in the penicillin and cephalosporin arts. Such esters may be prepared byconventional techniques known in the art.

Various forms of prodrugs are well known in the art. For examples ofsuch prodrug derivatives, see:

a) Design of Prodrugs, Bundgaard, H., ed. (Elsevier, 1985) and Methodsin Enzymology, Vol. 112, pp. 309-396, K. Widder, K. et al., eds.(Academic Press, 1985);

b) A Textbook of Drug Design and Development, Krosgaard-Larsen et al.,eds., and Bundgaard, H., Chapter 5, “Design and Application ofProdrugs”, pp. 113-191 (1991); and

c) Bundgaard, H., Advanced Drug Delivery Reviews, Vol. 8, pp. 1-38(1992), each of which is incorporated herein by reference.

Compounds of the formula (I) and salts thereof may exist in theirtautomeric form, in which hydrogen atoms are transposed to other partsof the molecules and the chemical bonds between the atoms of themolecules are consequently rearranged. It should be understood that theall tautomeric forms, insofar as they may exist, are included within theinvention.

Compounds of this invention may have one or more asymmetric centers.Unless otherwise indicated, all chiral (enantiomeric and diastereomeric)and racemic forms of compounds of the present invention are included inthe present invention. Many geometric isomers of olefins, C═N doublebonds, and the like can also be present in the compounds, and all suchstable isomers are contemplated in the present invention. Cis and transgeometric isomers of the compounds of the present invention aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. The present compounds can be isolated in opticallyactive or racemic forms. It is well known in the art how to prepareoptically active forms, such as by resolution of racemic forms or bysynthesis from optically active starting materials. All chiral,(enantiomeric and diastereomeric) and racemic forms and all geometricisomeric forms of a structure are intended, unless the specificstereochemistry or isomer form is specifically indicated. All geometricisomers, tautomers, atropisomers, hydrates, solvates, polymorphs, andisotopically labeled forms of the compounds referred to herein, andmixtures thereof, are considered within the scope of the presentinvention. Methods of solvation are generally known in the art.

Utility

The compounds of the invention modulate kinase activity, including themodulation of Btk. Other types of kinase activity that may be modulatedby the compounds of the instant invention include, but are not limitedto, the Tec family of compounds, such as Bmx, Btk, Itk, Txk and Tec, andmutants thereof.

Accordingly, compounds of formula (I) have utility in treatingconditions associated with the modulation of kinase activity, andparticularly the selective inhibition of Btk activity or the inhibitionof Btk and other Tec family kinases such as Itk. Such conditions includeB-cell mediated diseases in which cytokine levels are modulated as aconsequence of intracellular signaling. In another embodiment, compoundsof formula (I) have advantageous selectivity for Btk activity and otherTec family kinases such as Tec over Lck activity, preferably from atleast 20 fold to over 1,000 fold more selective.

As used herein, the terms “treating” or “treatment” encompass thetreatment of a disease state in a mammal, particularly in a human, andinclude: (a) preventing or delaying the occurrence of the disease statein a mammal, in particular, when such mammal is predisposed to thedisease state but has not yet been diagnosed as having it; (b)inhibiting the disease state, i.e., arresting its development; and/or(c) achieving a full or partial reduction of the symptoms or diseasestate, and/or alleviating, ameliorating, lessening, or curing thedisease or disorder and/or its symptoms.

In view of their activity as selective inhibitors of Btk or Btk andother Tec family kinase such as Itk, compounds of Formula (I) are usefulin treating cytokine-associated conditions including, but not limitedto, inflammatory diseases such as Crohn's and ulcerative colitis,asthma, graft versus host disease, chronic obstructive pulmonarydisease; autoimmune diseases such as Graves' disease, rheumatoidarthritis, systemic lupus erythematosis, psoriasis; destructive bonedisorders such as bone resorption disease, osteoarthritis, osteoporosis,multiple myeloma-related bone disorder; proliferative disorders such asacute myelogenous leukemia, chronic myelogenous leukemia; angiogenicdisorders such as angiogenic disorders including solid tumors, ocularneovasculization, and infantile haemangiomas; infectious diseases suchas sepsis, septic shock, and Shigellosis; neurodegenerative diseasessuch as Alzheimer's disease, Parkinson's disease, cerebral ischemias orneurodegenerative disease caused by traumatic injury, oncologic andviral diseases such as metastatic melanoma, Kaposi's sarcoma, multiplemyeloma, and HIV infection and CMV retinitis, AIDS, respectively.

More particularly, the specific conditions or diseases that may betreated with the inventive compounds include, without limitation,pancreatitis (acute or chronic), asthma, allergies, adult respiratorydistress syndrome, chronic obstructive pulmonary disease,glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosis,scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis,diabetes, autoimmune hemolytic anemia, autoimmune neutropenia,thrombocytopenia, atopic dermatitis, chronic active hepatitis,myasthenia gravis, multiple sclerosis, inflammatory bowel disease,ulcerative colitis, Crohn's disease, psoriasis, graft vs. host disease,inflammatory reaction induced by endotoxin, tuberculosis,atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis,Reiter's syndrome, gout, traumatic arthritis, rubella arthritis, acutesynovitis, pancreatic β-cell disease; diseases characterized by massiveneutrophil infiltration; rheumatoid spondylitis, gouty arthritis andother arthritic conditions, cerebral malaria, chronic pulmonaryinflammatory disease, silicosis, pulmonary sarcoisosis, bone resorptiondisease, allograft rejections, fever and myalgias due to infection,cachexia secondary to infection, meloid formation, scar tissueformation, ulcerative colitis, pyresis, influenza, osteoporosis,osteoarthritis, acute myelogenous leukemia, chronic myelogenousleukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma,sepsis, septic shock, and Shigellosis; Alzheimer's disease, Parkinson'sdisease, cerebral ischemias or neurodegenerative disease caused bytraumatic injury; angiogenic disorders including solid tumors, ocularneovasculization, and infantile haemangiomas; viral diseases includingacute hepatitis infection (including hepatitis A, hepatitis B andhepatitis C), HIV infection and CMV retinitis, AIDS, ARC or malignancy,and herpes; stroke, myocardial ischemia, ischemia in stroke heartattacks, organ hyposia, vascular hyperplasia, cardiac and renalreperfusion injury, thrombosis, cardiac hypertrophy, thrombin-inducedplatelet aggregation, endotoxemia and/or toxic shock syndrome,conditions associated with prostaglandin endoperoxidase syndase-2, andpemphigus vulgaris. Preferred methods of treatment are those wherein thecondition is selected from Crohn's and ulcerative colitis, allograftrejection, rheumatoid arthritis, psoriasis, ankylosing spondylitis,psoriatic arthritis, and pemphigus vulgaris. Alternatively preferredmethods of treatment are those wherein the condition is selected fromischemia reperfusion injury, including cerebral ischemia reperfusionsinjury arising from stroke and cardiac ischemia reperfusion injuryarising from myocardial infarction. Another preferred method oftreatment is one in which the condition is multiple myeloma.

In addition, the kinase inhibitors of the present invention inhibit theexpression of inducible pro-inflammatory proteins such as prostaglandinendoperoxide synthase-2 (PGHS-2), also referred to as cyclooxygenase-2(COX-2). Accordingly, additional Btk-associated conditions includeedema, analgesia, fever and pain, such as neuromuscular pain, headache,pain caused by cancer, dental pain and arthritis pain. The inventivecompounds also may be used to treat veterinary viral infections, such aslentivirus infections, including, but not limited to equine infectiousanemia virus; or retro virus infections, including felineimmunodeficiency virus, bovine immunodeficiency virus, and canineimmunodeficiency virus.

When the terms “Btk-associated condition” or “Btk-associated disease ordisorder” are used herein, each is intended to encompass all of theconditions identified above as if repeated at length, as well as anyother condition that is affected by Btk kinase activity.

The present invention thus provides methods for treating suchconditions, comprising administering to a subject in need thereof atherapeutically-effective amount of at least one compound of Formula (I)or a salt thereof “Therapeutically effective amount” is intended toinclude an amount of a compound of the present invention that iseffective when administered alone or in combination to inhibit Btk andother Tec family kinases and/or treat diseases.

The methods of treating Btk kinase-associated conditions may compriseadministering compounds of Formula (I) alone or in combination with eachother and/or other suitable therapeutic agents useful in treating suchconditions. Accordingly, “therapeutically effective amount” is alsointended to include an amount of the combination of compounds claimedthat is effective to inhibit Btk and/or treat diseases associated withBtk.

Exemplary of such other therapeutic agents include corticosteroids,rolipram, calphostin, cytokine-suppressive anti-inflammatory drugs(CSAIDs), Interleukin-10, glucocorticoids, salicylates, nitric oxide,and other immunosuppressants; nuclear translocation inhibitors, such asdeoxyspergualin (DSG); non-steroidal antiinflammatory drugs (NSAIDs)such as ibuprofen, celecoxib and rofecoxib; steroids such as prednisoneor dexamethasone; antiviral agents such as abacavir; antiproliferativeagents such as methotrexate, leflunomide, FK506 (tacrolimus, PROGRAF®);cytotoxic drugs such as azathiprine and cyclophosphamide; TNF-αinhibitors such as tenidap, anti-TNF antibodies or soluble TNF receptor,and rapamycin (sirolimus or RAPAMUNE®) or derivatives thereof.

The above other therapeutic agents, when employed in combination withthe compounds of the present invention, may be used, for example, inthose amounts indicated in the Physicians' Desk Reference (PDR) or asotherwise determined by one of ordinary skill in the art. In the methodsof the present invention, such other therapeutic agent(s) may beadministered prior to, simultaneously with, or following theadministration of the inventive compounds. The present invention alsoprovides pharmaceutical compositions capable of treating Btkkinase-associated conditions, including IL-1, IL-6, IL-8, IFNγ andTNF-α-mediated conditions, as described above.

The inventive compositions may contain other therapeutic agents asdescribed above and may be formulated, for example, by employingconventional solid or liquid vehicles or diluents, as well aspharmaceutical additives of a type appropriate to the mode of desiredadministration (e.g., excipients, binders, preservatives, stabilizers,flavors, etc.) according to techniques such as those well known in theart of pharmaceutical formulation.

Accordingly, the present invention further includes compositionscomprising one or more compounds of Formula (I) and a pharmaceuticallyacceptable carrier.

A “pharmaceutically acceptable carrier” refers to media generallyaccepted in the art for the delivery of biologically active agents toanimals, in particular, mammals. Pharmaceutically acceptable carriersare formulated according to a number of factors well within the purviewof those of ordinary skill in the art. These include without limitationthe type and nature of the active agent being formulated; the subject towhich the agent-containing composition is to be administered; theintended route of administration of the composition; and, thetherapeutic indication being targeted. Pharmaceutically acceptablecarriers include both aqueous and non-aqueous liquid media, as well as avariety of solid and semi-solid dosage forms. Such carriers can includea number of different ingredients and additives in addition to theactive agent, such additional ingredients being included in theformulation for a variety of reasons, e.g., stabilization of the activeagent, binders, etc., well known to those of ordinary skill in the art.Descriptions of suitable pharmaceutically acceptable carriers, andfactors involved in their selection, are found in a variety of readilyavailable sources such as, for example, Remington's PharmaceuticalSciences, 17th Edition (1985), which is incorporated herein by referencein its entirety.

The compounds of Formula (I) may be administered by any means suitablefor the condition to be treated, which may depend on the need forsite-specific treatment or quantity of drug to be delivered. Topicaladministration is generally preferred for skin-related diseases, andsystematic treatment preferred for cancerous or pre-cancerousconditions, although other modes of delivery are contemplated. Forexample, the compounds may be delivered orally, such as in the form oftablets, capsules, granules, powders, or liquid formulations includingsyrups; topically, such as in the form of solutions, suspensions, gelsor ointments; sublingually; bucally; parenterally, such as bysubcutaneous, intravenous, intramuscular or intrasternal injection orinfusion techniques (e.g., as sterile injectable aq. or non-aq.solutions or suspensions); nasally such as by inhalation spray;topically, such as in the form of a cream or ointment; rectally such asin the form of suppositories; or liposomally. Dosage unit formulationscontaining non-toxic, pharmaceutically acceptable vehicles or diluentsmay be administered. The compounds may be administered in a formsuitable for immediate release or extended release. Immediate release orextended release may be achieved with suitable pharmaceuticalcompositions or, particularly in the case of extended release, withdevices such as subcutaneous implants or osmotic pumps.

Exemplary compositions for topical administration include a topicalcarrier such as PLASTIBASE® (mineral oil gelled with polyethylene).

Exemplary compositions for oral administration include suspensions whichmay contain, for example, microcrystalline cellulose for imparting bulk,alginic acid or sodium alginate as a suspending agent, methylcelluloseas a viscosity enhancer, and sweeteners or flavoring agents such asthose known in the art; and immediate release tablets which may contain,for example, microcrystalline cellulose, dicalcium phosphate, starch,magnesium stearate and/or lactose and/or other excipients, binders,extenders, disintegrants, diluents and lubricants such as those known inthe art. The inventive compounds may also be orally delivered bysublingual and/or buccal administration, e.g., with molded, compressed,or freeze-dried tablets. Exemplary compositions may includefast-dissolving diluents such as mannitol, lactose, sucrose, and/orcyclodextrins. Also included in such formulations may be high molecularweight excipients such as celluloses (AVICEL®) or polyethylene glycols(PEG); an excipient to aid mucosal adhesion such as hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC), sodiumcarboxymethyl cellulose (SCMC), and/or maleic anhydride copolymer (e.g.,GANTREZ®); and agents to control release such as polyacrylic copolymer(e.g., CARBOPOL 934®). Lubricants, glidants, flavors, coloring agentsand stabilizers may also be added for ease of fabrication and use.

Exemplary compositions for nasal aerosol or inhalation administrationinclude solutions which may contain, for example, benzyl alcohol orother suitable preservatives, absorption promoters to enhance absorptionand/or bioavailability, and/or other solubilizing or dispersing agentssuch as those known in the art.

Exemplary compositions for parenteral administration include injectablesolutions or suspensions which may contain, for example, suitablenon-toxic, parenterally acceptable diluents or solvents, such asmannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodiumchloride solution, or other suitable dispersing or wetting andsuspending agents, including synthetic mono- or diglycerides, and fattyacids, including oleic acid.

Exemplary compositions for rectal administration include suppositorieswhich may contain, for example, suitable non-irritating excipients, suchas cocoa butter, synthetic glyceride esters or polyethylene glycols,which are solid at ordinary temperatures but liquefy and/or dissolve inthe rectal cavity to release the drug.

The therapeutically-effective amount of a compound of the presentinvention may be determined by one of ordinary skill in the art, andincludes exemplary dosage amounts for a mammal of from about 0.05 to1000 mg/kg; 1-1000 mg/kg; 1-50 mg/kg; 5-250 mg/kg; 250-1000 mg/kg ofbody weight of active compound per day, which may be administered in asingle dose or in the form of individual divided doses, such as from 1to 4 times per day. It will be understood that the specific dose leveland frequency of dosage for any particular subject may be varied andwill depend upon a variety of factors, including the activity of thespecific compound employed, the metabolic stability and length of actionof that compound, the species, age, body weight, general health, sex anddiet of the subject, the mode and time of administration, rate ofexcretion, drug combination, and severity of the particular condition.Preferred subjects for treatment include animals, most preferablymammalian species such as humans, and domestic animals such as dogs,cats, horses, and the like. Thus, when the term “patient” is usedherein, this term is intended to include all subjects, most preferablymammalian species, that are affected by mediation of Btk enzyme levels.

Biological Assays

Human Recombinant Btk Enzyme Assay

To V-bottom 384-well plates were added test compounds, human recombinantBtk (1 nM, Invitrogen Corporation), fluoresceinated peptide (1.5 μM),ATP (20 μM), and assay buffer (20 mM HEPES pH 7.4, 10 mM MgCl₂, 0.015%Brij35 and 4 mM DTT in 1.6% DMSO), with a final volume of 30 μL. Afterincubating at room temperature for 60 min, the reaction was terminatedby adding 45 μl of 35 mM EDTA to each sample. The reaction mixture wasanalyzed on the Caliper LABCHIP® 3000 (Caliper, Hopkinton, Mass.) byelectrophoretic separation of the fluorescent substrate andphosphorylated product. Inhibition data were calculated by comparison tono enzyme control reactions for 100% inhibition and no inhibitorcontrols for 0% inhibition. Dose response curves were generated todetermine the concentration required inhibiting 50% of kinase activity(IC₅₀). Compounds were dissolved at 10 mM in dimethylsulfoxide (DMSO)and evaluated at eleven concentrations.

Using this assay, the IC₅₀ values of the following compounds weredetermined. See Table 1.

TABLE 1 IC₅₀ for Inhibition Example of Btk, nM 9 2 11 3 30 3 32 7 34 735 57 36 3 37 14 41 6 42 521 54 65 55 43 56 32 60 85 64 8 71 3 87 7 99 8110 14 117 23Mouse Splenic B Cell Proliferation Assay

Spleens from Balb/c mice (<12 weeks old) were mashed through screens andred blood cells were removed from splenocytes with RBC lysing buffer(Sigma-Aldrich Chemical Co, St. Louis, Mo.). T cells were depleted byincubation on nylon wool columns (Wako, Richmond, Va.). Resultingsplenic B cells prepared this way were routinely >90% CD19⁺ as measuredby FACS analysis. B cells (1×10⁵ cells per well) were added to serialdilutions of compounds in triplicate in 96-well flat-bottom plates inRPMI 1640 (Invitrogen, Grand Island, N.Y.), supplemented with 10%heat-inactivated fetal calf serum (FCS, Summit Biotechnology, FortCollins, Colo.), containing 1% L-glutamine (Invitrogen), 50 μg/mlgentamicin (Invitrogen) and 5×10⁻⁵M β-mercaptoethanol (Sigma-Aldrich).Cells were stimulated with 10 μg/ml of Affinipure F(ab′)₂ fragment goatanti-mouse IgG IgM (Jackson Immunoresearch, West Grove, Pa.). Cultureswere incubated for 72 hours, and pulsed for the last 6 hours with oneμCi/well of ³[H]-thymidine (PerkinElmer, Boston, Mass.) prior to harveston a Packard cell harvester (PerkinElmer), and counted by liquidscintillation on a Packard TOPCOUNT® NXT (PerkinElmer). The most potentanalogs were found to be active below 1 μM.

Human Tonsillar B Cell Proliferation Assay

Tonsils were excised from patients undergoing routine tonsillectomy.Tonsil tissue was minced, mashed through screens and mononuclear cellswere isolated on ficoll density gradients (Lymphocyte Separation Media;Mediatech Inc., Herndon, Va.). T cells were depleted from mononuclearcells by rosetting with sheep red blood cells (SRBC, Colorado SerumCompany; Denver, Colo.). Tonsillar B cells prepared by this method wereroutinely >95% CD19⁺ as measured by FACS analysis. B cells (1×10⁵ cellsper well) were added to serial dilutions of compounds in triplicate in96-well flat-bottom plates in RPMI 1640, (Invitrogen, Grand Island,N.Y.), supplemented with 10% heat-inactivated fetal calf serum (FCS,Summit Biotechnology, Fort Collins, Colo.), and containingantibiotic/antimycotic (Invitrogen, 1:100 dilution) and gentamicin(Invitrogen, 5 μg/ml). Cells were stimulated with 40 μg/ml AffinPureF(ab′)2 Fragment Goat anti Human IgG+IgM (Jackson Immunoresearch, WestGrove, Pa.) in a total volume of 0.2 ml. Cultures were incubated for 72hours, and pulsed for the last 6 hours with one μCi/well of³[H]-thymidine (PerkinElmer, Boston, Mass.) prior to harvest on aPackard cell harvester (PerkinElmer), and counted by liquidscintillation on a Packard TOPCOUNT® NXT (PerkinElmer).

Btk Phosphorylation Assay

Ramos cells (˜6×10⁶ cells/ml) were incubated in the presence of Btkinhibitors for 1 hr at 37° C. before being stimulated with anti-humanIgM+IgG (F(ab′)2 fragment, Jackson ImmunoResearch, catalog #109-006-127)at 50 μg/mL for exactly 2 min at 37° C. Cells were immediately fixed byadding an equal volume of pre-warmed BD Phosflow Fix Buffer I (BDBiosciences, catalog number 557870) to the cell suspension. Afterincubating at 37° C. for 10 minutes, the cells were washed once with 3mL FACS washing buffer (1% FBS/PBS) and permeabilized by adding 0.5 mLof cold BD Phosflow Perm Buffer III (BD Biosciences, catalog number558050) and incubating for 30 minutes on ice. The cells were washed anadditional two times with 3 mL BD FACS washing buffer, re-suspended in100 μL FACS washing buffer, stained with 20 μL Alexa647 anti-Btk (pY551)(BD Biosciences, catalog number 558134), incubated at room temperaturefor 30 minutes in the dark, and washed once with 3 ml of FACS washingbuffer. The cells were re-suspended in 400 μl FACS wash buffer andanalyzed using FACSCalibur (BD Biosciences). Median fluorescentintensity (MFI) on Alexa 647 (FL-4) data were collected and used forcalculations of inhibition.

Ramos FLIPR® Assay

Ramos RA1 B cells (ATCC CRL-1596) at a density of 2×10⁶ cells/ml in RPMIminus phenol red (Invitrogen 11835-030) and 50 mM HEPES (Invitrogen15630-130) containing 0.1% BSA (Sigma A8577) were added to one halfvolume of calcium loading buffer (BD bulk kit for probenecid sensitiveassays, #640177) and incubated at room temperature in the dark for 1hour. Dye-loaded cells were pelleted (Beckmann GS-CKR, 1200 rpm, RT, 5minutes) and resuspended in RT RPMI minus phenol red with 50 mM HEPESand 10% FBS to a density of 1×10⁶ cells/ml. 150 μl aliquots(150,000/well) were plated into 96 well poly-D-lysine coated assayplates (BD 35 4640) and briefly centrifuged (Beckmann GS-CKR 800 rpm, 5minutes, without brake). 50 μl compound dilutions in 0.4% DMSO/RPMIminus phenol red+50 mM HEPES+10% FBS were added to the wells and theplate was incubated at RT in the dark for 1 hour. Assay plate wasbriefly centrifuged as above prior to measuring calcium levels.

Using the FLIPR1 (Molecular devices), cells were stimulated by addinggoat anti-human IgM (Invitrogen AHI0601) to 2.5 μg/mL. Changes inintracellular calcium concentrations were measured for 180 seconds andpercent inhibition was determined relative to peak calcium levels seenin the presence of stimulation only. Biological activity of certaincompounds as assessed using this assay is shown in Table 2.

TABLE 2 IC50 for Inhibition of Ramos FLIPR ® Example assay, nM 25 62 3016 31 71 35 1,382 37 190 41 >500 42 >1000 71 71 73 1,031 77 81 79 856 821,078 85 1,417 87 63 90 84 92 56 97 15 100 19 110 96 117 294NFAT-bla RA1 Reporter Assay

Ramos B cells containing a stable integration of a beta-lactamasereporter gene under the control of an NFAT response element (NFAT-blaRA1, Invitrogen, K1434) at a density of 100×103 cells/well wereincubated with test compounds at 37° C. for 30 min prior to stimulationwith F(ab′)2 anti-human IgM (Jackson ImmunoResearch, 109-006-129) at 2.5μg/ml for 4.5 hrs at 37° C. After stimulation, LiveBLAzer-FRET B/GSubstrate (CCF2/AM, or CCF4/AM, Invitrogen) was added to each well andincubated for 90 min at room temperature in the dark. Assay plates wereread on an LJL Analyst, with raw emission values subtracted from amedia-only blank containing substrate in assay media (no cells). Theratios of 460 nm/530 nm emission (405 nm excitation) were used tocalculate the amount of stimulation.

KLH Antigen Challenge and Antibody Measurement

Female BALB/c mice (6-8 weeks old) were immunized intraperitoneally (IP)with 250 μg keyhole limit hemocyanin (KLH) (Pierce, Rockford, Ill.) inphosphate-buffered saline (PBS). Mice in appropriate groups were dosedas indicated. Blood was collected 14 days post-immunization, serum wasseparated and analyzed for anti-KLH IgG titers by ELISA. Briefly, 96well plates were coated with KLH in PBS, blocked, and serial dilutionsof test serum samples were added. Captured anti-KLH antibodies weredetected using horseradish peroxidase-conjugated antibody specific formouse IgG (Southern Biotechnology Associates, Birmingham, Ala.) and theTMB peroxidase substrate system (Kirkegaard and Perry Laboratories,Gaithersburg, Md.). Optical densities of developed plates werequantitated in a SPECTRAMAX® Plus ELISA plate reader (Molecular Devices,Sunnyvale, Calif.). When administered twice daily, the compound ofExample 76-15 inhibited the anti-KLH IgG response by 29% and 56% at 10mg/kg and 30 mg/kg, respectively.

Methods of Preparation

Compounds of Formula (I), and intermediates used in the preparation ofcompounds of Formula (I), can be prepared using procedures shown in thefollowing examples and related procedures. The methods and conditionsused in these examples, and the actual compounds prepared in theseexamples, are not meant to be limiting, but are meant to demonstrate howthe compounds of Formula (I) can be prepared. Starting materials andreagents used in these examples, when not prepared by a proceduredescribed herein, are generally either commercially available, or arereported in the chemical literature, or may be prepared by usingprocedures described in the chemical literature.

In the examples given, the phrase “dried and concentrated” generallyrefers to drying of a solution in an organic solvent over either sodiumsulfate or magnesium sulfate, followed by filtration and removal of thesolvent from the filtrate (generally under reduced pressure and at atemperature suitable to the stability of the material being prepared).Column chromatography was performed with pre-packed silica gelcartridges using an ISCO medium pressure chromatography apparatus(Teledyne Corporation), eluting with the solvent or solvent mixtureindicated. Preparative high performance liquid chromatography (HPLC) wasperformed using a reverse phase column (Waters Sunfire C₁₈, WatersXbridge C₁₈, PHENOMENEX® Axia C₁₈, YMC S5 ODS or the like) of a sizeappropriate to the quantity of material being separated, generallyeluting with a gradient of increasing concentration of methanol oracetonitrile in water, also containing 0.05% or 0.1% trifluoroaceticacid or 10 mM ammonium acetate, at a rate of elution suitable to thecolumn size and separation to be achieved. Chemical names weredetermined using ChemDraw Ultra, version 9.0.5 (CambridgeSoft). Thefollowing abbreviations are used:

-   NaHCO₃ (aq)—saturated aqueous sodium bicarbonate-   brine—saturated aqueous sodium chloride-   DCM—dichloromethane-   DIEA—N,N-diisopropylethylamine-   DMAP—4-(N,N-dimethylamino)pyridine-   DMF—N,N-dimethylformamide-   DMSO—dimethyl sulfoxide-   EDC—N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride-   EtOAc—ethyl acetate-   HOAT—1-hydroxy-7-azabenzotriazole-   HOBT—1-hydroxybenzotriazole hydrate-   rt—ambient room temperature (generally about 20-25° C.).-   TEA—triethylamine-   TFA—trifluoroacetic acid-   THF—tetrahydrofuran

Schemes

The compounds of Formula (I) may be prepared according to the followingschemes and the knowledge of one skilled in the art.

The compounds of Formula (1-1) can be prepared according to Scheme 1.Michael addition of indole 1 to nitro olefin 2 at melting conditionsprovides nitro intermediate 3. In some cases, the addition can also beeffected in solution with or without a catalyst such astris(trifluoromethylsulfonyloxy)ytterbium and indium (III) bromide.Reduction of 3 by hydrogenation with Raney Ni affords amine 4. Thisconversion can also be realized with zinc dust and ammonium chloride.Treatment of 4 with ethyl 2-oxoacetate in the presence of hydrogenchloride gives 5, which is aromatized with Pd/C to form β-carbolinesystem 6. Hydrolysis of 6 and subsequent primary amide formationsupplies target or target precursor 7. When necessary, compound 7 isfurther elaborated to (1-1) by methods known to those skilled in theart.

The compounds of Formula (1-2) can be prepared according to Scheme 2.Treatment of aniline 8 with benzyl chloroformate in the presence ofpotassium carbonate gives rise to 9. The latter is treated with Dibal-Hto form benzaldhyde 10. Reaction of 10 with nitroalkane in the presenceof ammonium acetate furnishes nitro olefin 11. Heating 11 with indole 1(Scheme 1) at melting conditions or in a solution with or without acatalyst such as tris(trifluoromethylsulfonyloxy)ytterbium and indium(III) bromide leads to the formation of indole derivative 12. Carbolineintermediate 13 is then obtained from 12 in the same way as 6 isobtained from 3 (Scheme 1). Removal of the Cbz group in 13 providesintermediate 14, which is converted to target or target precursor 15.When necessary, compound 15 is further elaborated to (1-2).

The compounds of Formula (1-2) can also be prepared according to Scheme3. Aniline 8 can be converted to 16 in the same way as 14 is convertedto 15 (Scheme 2). Treatment of 16 with Dibal-H produces benzaldhyde 17,which is converted to nitro olefin 18 with nitromethane in the presenceof ammonium acetate. Heating 18 with indole 1 (Scheme 1) at meltingconditions or in a solution with or without a catalyst such astris(trifluoromethylsulfonyloxy)ytterbium and indium (III) bromidegenerates indole derivative 19. Target or target precursor 15 can bederived from 19 in the same way as compound 6 is derived from 3 (Scheme1). When necessary, compound 15 is further elaborated to (1-2).

The compounds of Formula (1-3) can be prepared according to Scheme 4.Friedel-Crafts reaction of indole 20 with 2-methyl-3-nitrobenzoylchloride in the presence of Lewis acid such as tin (IV) chloride affordsketo-ester 21. Reaction of 21 with hydrazine provides intermediate 22,which is converted to chloro pyridazinoindole 23 with POCl₃. Treatmentof 23 in a steel bomb with CO (g) in the presence of1,1′-bis(diphenylphosphino)ferrocene (DPPF) and palladium (II) acetateresults in the formation of 24. During the reaction, the nitro group in23 is reduced to amino at the same time. Direct conversion of ester 24to primary amide 25 is achieved with concentrated ammonia in methanol atelevated temperature. Compound 25 is then transformed into target ortarget precursor 26 in the same way as 14 is converted to 15 (Scheme 2).When necessary, compound 26 is further elaborated to (1-3).

The compounds of Formula (1-4) can be prepared according to Scheme 5.Compound 28 is obtained from indole 27 in the same way as 22 is obtainedfrom 20 (Scheme 4). Stille reaction of 28 with tributyl(1-ethoxyvinyl)stannane in the presence ofdichlorobis(triphenylphosphine)-palladium(II) supplies 29. Treatment of29 with POCl₃ provides chloro pyridazinoindole 30, which is converted toprecursor 31. Grignard reagent or lithium reagent addition to 31completes the synthesis of (1-4).

The compounds of Formula (1-6) can be prepared according to Scheme 6.The preparation of 36 is described in the literature. Intermediate 36 iscarbonylated under pressure to give 37, which is brominated to give 38.Treatment of 38 with copper cyanide at high temperature gives 39 whichon treatment with phosphorous oxychloride gave 40. 40 is coupled underSuzuki conditions with the requisite boronic acid to give 41, thecyano-group of which is later hydrolyzed under acidic conditions to give42. The ester functionality of 42 on treatment with methyl lithium canbe further elaborated to (1-6).

Compounds of Formula (1-7) can be prepared according to Scheme 7.Treatment of hydrazine 43 with a suitably protected 4-piperidone 44(where P can be, for example, ethoxycarbonyl) in the presence of an acidcatalyst can provide 45 in a reaction commonly referred to as theFischer indole synthesis. As desired, the protecting group P of 45 canbe removed and replaced with an alternative protecting group such astriphenylmethyl. Treatment of 45 with an organolithium reagent such astert-butyl lithium, followed by treatment with trimethylsilylisocyanate, can provide the amide 46. Coupling of 46 with a suitableboronic acid or boronic acid ester, using an appropriate base and anappropriate palladium-containing catalyst (commonly known as the Suzukireaction), can provide 47. Removal of the protecting group P undersuitable conditions can provide compounds of Formula (1-7) where R′ isH. Treatment of compounds of Formula (1-7) where R′ is H with a suitablereagent such as a carboxylic acid anhydride, carboxylic acid chloride,sulfonyl chloride, carbamoyl chloride or chloroformate can providecompounds of Formula (1-7) where R′ is an acyl, sulfonyl, carbamoyl oralkoxycarbonyl group, respectively.

Compounds of Formula (1-8) can be prepared according to Scheme 8.Compounds of Formula (1-7) where R′ is H can be treated with anappropriate oxidizing agent such as, for example, manganese dioxide or2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) to provide Compounds ofFormula (1-8).

Compounds of Formula (1-9) can be prepared according to Scheme 9.Treatment of 1,4-dibromo-2-nitrobenzene 48 with vinylmagnesium bromide49 can provide 50 in a reaction commonly referred to as the Bartoliindole synthesis. Treatment of 50 with an organolithium reagent such asbutyllithium, followed by treatment with carbon dioxide, can provide thecarboxylic acid 51. Treatment of 51 with ammonium hydroxide, EDC, andHOBT can provide amide 52. Treatment of 52 withN,N-dimethyl-2-nitroethenamine can provide 53, which can be reduced withlithium aluminum hydride to provide 54. Treatment of 54 withformaldehyde in the presence of aqueous HCl can provide 55. Compounds 56can be prepared similarly to the preparation of compound 47 in Scheme 7.Compounds of Formula (1-9) can be prepared from 56 using the procedureshown in Scheme 8.

Compounds of Formula (1-10) can be prepared according to Scheme 10.Treatment of 57 with paraformaldehyde and dimethylamine in acetic acidcan provide 58. Treatment of 58 with ethyl 2-nitroacetate and methylpropiolate (following the procedure of Jones et al., Tetrahedron Lett.,48:1291 (2007)) can provide 59, which can be reduced by zinc dust toproduce 60. Treatment of 60 with formaldehyde in the presence of aqueousHCl can provide 61. 61 can be converted to 62 by the method shown inScheme 8. Treatment of 62 with a suitable reagent such as lithiumaluminum hydride, methylithium, or sodium hydroxide can provide 63 whereR′ is hydroxymethyl, 2-hydroxypropan-2-yl, or carboxylic acid,respectively. Compound 63 where R′ is carboxylic acid can also beconverted to the corresponding amides through a variety of well-knownamide forming reactions. Compounds of Formula (1-10) can be preparedfrom 63 as described in Scheme 7 for the preparation of compounds 47.

Compounds of Formula (1-11) can be prepared according to Scheme 11.Treatment of 51 with DMF and phosphorus oxychloride can provide 64.Treatment of 64 with ethyl 2-amino-3,3-diethoxypropanoate in thepresence of sodium triacetoxyborohydride can provide 65. Treatment of 65with titanium tetrachloride can provide 66, which can be converted to 67by using sodium perborate tetrahydrate. Coupling of 67 withdimethylamine in the presence of EDC and HOAt can provide 68, which canbe converted to compounds of Formula (1-11) as described for thepreparation of 47 in Scheme 7.

Compounds of Formula (1-12) can be prepared according to Scheme 12.Treatment of 67 with methanol in the presence of EDC and HOAt canprovide 69. Intermediate 69 can be reduced by lithium aluminum hydride,and the intermediate can then be reacted with a suitable boronic acid orboronic acid ester as describe in preparation of compound 47 in Scheme 7to provide compounds of Formula (1-12).

EXAMPLES 1 and 24-(2-Fluorophenyl)-7-morpholino-9H-pyrido[3,4-b]indole-1-carboxamide,and8-Chloro-4-(2-fluorophenyl)-7-morpholino-9H-pyrido[3,4-b]indole-1-carboxamide

1. 4-(1H-indol-6-yl)morpholine

A mixture of 1H-indol-6-amine (3.14 g, 23.76 mmol),1-chloro-2-(2-chloroethoxy)ethane (4.18 mL, 35.6 mmol), and sodiumcarbonate (10.07 g, 95 mmol) in t-BuOH (90 mL) was heated at 100° C. ina pressure tube for 3.5 days. On cooling to room temperature, themixture was diluted with ethyl acetate and filtered through CELITE®. Thefiltrate was concentrated under vacuum to dryness. To the residue wasadded water (50 mL). The mixture was adjusted to pH 11 with saturatedNaHCO₃ solution and extracted with CH₂Cl₂ (4×80 mL). The combinedextract was washed with brine (50 mL) and dried over anhydrous MgSO₄.The desired product (3.96 g, 19.58 mmol, 82% yield) was isolated as abeige solid with ISCO (300 g silica gel, solid loading, 20-50% ethylacetate/hexane).

2. 4-(3-(1-(2-Fluorophenyl)-2-nitroethyl)-1H-indol-6-yl)morpholine

A mixture of 4-(1H-indol-6-yl)morpholine (0.300 g, 1.483 mmol) and(E)-1-fluoro-2-(2-nitrovinyl)benzene (0.372 g, 2.225 mmol) in toluene (8mL) was heated in a pressure tube at 150° C. for 2 days. The solvent wasremoved under vacuum, and the residue was subjected to ISCO (80 g silicagel, solid loading, 30-60% ethyl acetate/hexane) to provide the desiredproduct (0.239 g, 0.647 mmol, 43.6% yield) as a tan solid.

3. 2-(2-Fluorophenyl)-2-(6-morpholino-1H-indol-3-yl)ethanamine

A mixture of4-(3-(1-(2-fluorophenyl)-2-nitroethyl)-1H-indol-6-yl)morpholine (0.235g, 0.636 mmol) and Raney Ni (a small spatula) in MeOH (30 mL) wastreated with hydrogen at 55 psi in a Parr shaker apparatus for 3 hr. Thecatalyst was removed by suction filtration. The filtrate wasconcentrated under vacuum, diluted with CH₂Cl₂ (100 mL), washed withbrine (25 mL) and dried over anhydrous MgSO₄. Removal of solvent undervacuum provided the desired product (0.181 g, 0.533 mmol, 84% yield) asan off-white solid.

4. Ethyl4-(2-fluorophenyl)-7-morpholino-9H-pyrido[3,4-b]indole-1-carboxylate

To a solution of2-(2-fluorophenyl)-2-(6-morpholino-1H-indol-3-yl)ethanamine (0.181 g,0.533 mmol) and ethyl 2-oxoacetate in toluene (50%) (0.233 mL, 1.173mmol) in 1,4-dioxane (18 mL) at room temperature was added hydrogenchloride (4 N in 1,4-dioxane) (0.267 mL, 1.067 mmol). The solutionturned heterogeneous and it was stirred at room temperature for 16 hr.The volatiles were removed under vacuum. The residue was diluted withwater (20 mL), basified with saturated NaHCO₃ solution to pH 10, andextracted with ethyl acetate (3×30 mL). The combined extract was washedwith brine (25 ml), dried over anhydrous MgSO₄, and concentrated todryness under vacuum. To the residue were added toluene (10 mL) and 10%Pd/C (0.3 g), and the mixture was heated at 140° C. under an ambientatmosphere for 4.5 hr. The solid phase was removed by suctionfiltration. The filtrate was diluted with ethyl acetate (100 ml), washedwith brine (25 ml), and dried over anhydrous MgSO₄. The desired product(94 mg, 0.222 mmol, 41.6% yield) was isolated with ISCO (24 g silicagel, 30-60% ethyl acetate/hexane) as a tan solid.

5. 4-(2-Fluorophenyl)-7-morpholino-9H-pyrido[3,4-b]indole-1-carboxylicacid

To a solution of ethyl4-(2-fluorophenyl)-7-morpholino-9H-pyrido[3,4-b]indole-1-carboxylate (94mg, 0.224 mmol) in MeOH (5 mL) at room temperature was added 1N sodiumhydroxide solution (1.121 mL, 1.121 mmol). The mixture was heated atreflux for 1 hr and then concentrated under vacuum. To the residue wasadded water (20 mL), and the resulting mixture was neutralized with 1 NHCl solution to pH 5. The precipitating product (68 mg, 0.172 mmol, 77%yield) was collected as a tan solid by suction filtration and dried at50° C. under vacuum.

6. 4-(2-Fluorophenyl)-7-morpholino-9H-pyrido[3,4-b]indole-1-carboxamideand8-chloro-4-(2-fluorophenyl)-7-morpholino-9H-pyrido[3,4-b]indole-1-carboxamide

To 4-(2-fluorophenyl)-7-morpholino-9H-pyrido[3,4-b]indole-1-carboxylicacid (63 mg, 0.161 mmol) at 0° C. was added sulfurous dichloride (19.15mg, 0.161 mmol). The mixture was stirred at room temperature for 1 hr,at which point a mixture of the following components were identified inthe reaction mixture with HPLC and LCMS.

The reaction was stopped by removing thionyl chloride under vacuum. Tothe residue was added toluene, and the volatiles were removed againunder vacuum. Then, to the residue was added ammonium chloride (34.4 mg,0.644 mmol), N,N-diisopropylamine (0.169 mL, 0.966 mmol), BOP (107 mg,0.241 mmol), and DMF (3 mL). The mixture was stirred at room temperaturefor 1.5 hr, diluted with ethyl acetate (60 mL), washed with water (3×15mL), and brine (15 mL). The organic solution was concentrated undervacuum, and the residue was subjected to prep. HPLC. The correspondingfractions were concentrated under vacuum, basified with saturated NaHCO₃solution. The precipitating products,4-(2-fluorophenyl)-7-morpholino-9H-pyrido[3,4-b]indole-1-carboxamide(3.97 mg, 9.97 μmol, 6.19% yield) and8-chloro-4-(2-fluorophenyl)-7-morpholino-9H-pyrido[3,4-b]indole-1-carboxamide(11.7 mg, 0.027 mmol, 16.94% yield), were collected as a tan solid and abeige solid, respectively, by suction filtration and dried at 55° C.under vacuum.

Analytical data for4-(2-fluorophenyl)-7-morpholino-9H-pyrido[3,4-b]indole-1-carboxamide:LCMS (M+H)⁺=391.10. Analytical data for8-chloro-4-(2-fluorophenyl)-7-morpholino-9H-pyrido[3,4-b]indole-1-carboxamide:LCMS (M+H)⁺=425.05. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ: 8.31 (s, 1H),7.67-7.60 (m, 2H), 7.48-7.43 (m, 2H), 7.22 (dd, J1=8.4 Hz, J2=1.8 Hz,1H), 6.98 (d, J=8.4 Hz, 1H), 3.76-3.73 (m, 4H), 3.06-3.02 (m, 4H).

EXAMPLE 34-(2-Fluorophenyl)-7-(morpholine-4-carbonyl)-9H-pyrido[3,4-b]indole-1-carboxamide

1. (1H-Indol-6-yl)(morpholino)methanone

A solution of morpholine (1.320 mL, 15.14 mmol), 1H-indole-6-carboxylicacid (2.0332 g, 12.62 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (3.63g, 18.92 mmol), 1-hydroxybenzotriazole (HOBt) (2.90 g, 18.92 mmol) anddiisopropylethylamine (DIPEA) (6.61 mL, 37.8 mmol) in DMF (31.5 mL) wasstirred overnight. The reaction was poured into a 1:1 water:brinesolution and extracted with EtOAc (2×). The organic layers were combinedand washed with 0.25 M aqueous KHSO₄, water, brine and 10% aqueous LiCl;dried over Na₂SO₄, filtered and concentrated in vacuo. Trituration withEt₂O provided the desired product (2.20 g, 9.58 mmol, 76% yield) as alight tan solid.

2.(3-(1-(2-Fluorophenyl)-2-nitroethyl)-1H-indol-6-yl)(morpholino)methanone

A sealed tube containing (1H-indol-6-yl)(morpholino)methanone (0.6323 g,2.75 mmol) and (E)-1-fluoro-2-(2-nitrovinyl)benzene (0.551 g, 3.30 mmol)in toluene (14 mL) was stirred at 150° C. for 4 days. The reaction wascooled and concentrated in vacuo to give a residue which was purified byflash chromatography using an ISCO 80 g column eluting with 0-100%EtOAc/hexanes. Appropriate fractions (100% elution) were collected andconcentrated in vacuo to give the desired product (0.222 g, 0.508 mmol,18.5% yield).

3.(3-(2-Amino-1-(2-fluorophenyl)ethyl)-1H-indol-6-yl)(morpholino)methanone

To a spatula full of Raney-Ni in a Parr tube was added a solution of(3-(1-(2-fluorophenyl)-2-nitroethyl)-1H-indol-6-yl)(morpholino)methanone(0.3659 g, 0.921 mmol) in MeOH (30.7 mL). The reaction was shaken underhydrogenation at 53 psi for 3 hr. After flushing with nitrogen, themixture was filtered through a pad of CELITE® and rinsed with MeOH. Thefiltrate was concentrated in vacuo to give the desired product (0.270 g,0.596 mmol, 64.7% yield).

4. Ethyl4-(2-fluorophenyl)-7-(morpholine-4-carbonyl)-9H-pyrido[3,4-b]indole-1-carboxylate

To a yellow, homogeneous solution of(3-(2-amino-1-(2-fluorophenyl)ethyl)-1H-indol-6-yl)(morpholino)methanone(0.270 g, 0.736 mmol) and 50% ethyl 2-oxoacetate/toluene (0.321 mL,1.619 mmol) in 1,4-dioxane (30 mL) was added 4 N HCl/dioxane (0.368 mL,1.472 mmol) under nitrogen, and the reaction was stirred overnight. Thereaction was concentrated in vacuo, diluted with water and basified topH ˜10 (by litmus paper) with NaHCO₃. This was extracted with EtOAc(3×), and the organic layers were combined and washed with brine, driedover MgSO₄, filtered and concentrated in vacuo to give crude productwhich was used in the subsequent step. This was combined with 10% Pd/C(0.710 g, 0.668 mmol) in toluene (10 mL), and the solution was refluxed.After 45 min, the reaction was cooled to room temperature and filteredthrough a pad of CELITE®, rinsing with EtOAc. The filtrate was washedwith brine, dried over MgSO₄, filtered and concentrated in vacuo to givea residue which was purified by flash chromatography using an ISCO 24 gcolumn eluting with 0-100% EtOAc/hexanes. Appropriate fractions werecollected and concentrated in vacuo to give the desired product (0.0592g, 0.132 mmol, 19.8% yield) as an off-white solid.

5.4-(2-Fluorophenyl)-7-(morpholine-4-carbonyl)-9H-pyrido[3,4-b]indole-1-carboxylicacid

To a yellow, homogeneous solution of ethyl4-(2-fluorophenyl)-7-(morpholine-4-carbonyl)-9H-pyrido[3,4-b]indole-1-carboxylate(0.0592 g, 0.132 mmol) in THF (2.84 mL) and MeOH (0.945 mL) was addedLiOH (0.022 g, 0.529 mmol) in water (0.5 mL). After 2 hr, the reactionmixture was concentrated in vacuo, and the residue was diluted withwater and acidified with 1N aq. HCl to pH ˜4 by litmus paper. Themixture was extracted with EtOAc (3×), and the organic layers werecombined, dried over Na₂SO₄, and concentrated in vacuo to give thedesired product (0.0382 g, 0.091 mmol, 68.8% yield) as a yellow solid.

6.4-(2-Fluorophenyl)-7-(morpholine-4-carbonyl)-9H-pyrido[3,4-b]indole-1-carboxamide

To a yellow, heterogeneous solution of4-(2-fluorophenyl)-7-(morpholine-4-carbonyl)-9H-pyrido[3,4-b]indole-1-carboxylicacid (0.0381 g, 0.091 mmol), ammonium chloride (9.72 mg, 0.182 mmol),HOAt (0.025 g, 0.182 mmol) and EDC (0.035 g, 0.182 mmol) in DMF (1.0 mL)was added DIPEA (0.063 mL, 0.364 mmol). The reaction was stirredovernight. EtOAc and water were added, and the layers were separated.The organic layer was washed with brine and 10% aq. LiCl successively,dried over Na₂SO₄, filtered and concentrated in vacuo to give a residuewhich was diluted with MeOH (1 mL) and subjected to autoprep reversephase HPLC purification. The appropriate fractions were combined,basified with NaHCO₃ (solid), and concentrated in vacuo. It wasextracted with CH₂Cl₂ (3×). The organic layers were combined, dried overNa₂SO₄, and concentrated in vacuo to give the desired product (0.0124 g,0.030 mmol, 32.6% yield) as a white solid. LC/MS (M+H)=419.08; ¹H NMR(500 MHz, DMSO-d₆) δ ppm 12.03 (s, 1H), 8.38 (br. S, 1H), 8.32 (s, 1H),7.89 (s, 1H), 7.86 (br. S, 1H), 7.63-7.75 (m, 2H), 7.44-7.58 (m, 2H),7.34 (d, J=8.2 Hz, 1H), 7.13 (d, J=8.2 Hz, 1H), 3.42-3.83 (m, 8H).

EXAMPLE 44-(2-Fluorophenyl)-7-methyl-6-(pyrimidin-5-yloxy)-9H-pyrido[3,4-b]indole-1-carboxamide

1. 1-Bromo-2,5-dimethyl-4-nitrobenzene

To a slurry of 2-bromo-1,4-dimethylbenzene (10.13 g, 54.7 mmol) inacetic acid (44 mL) at 8° C. (inner temperature) was added a solution ofnitric acid (6 mL, 134 mmol) in sulfuric acid (22 mL, 413 mmol) over 45min; temperature rose to 10° C. After 1 hr, the reaction mixture waspoured into ice and stirred, filtered and washed with water to give alight yellow solid. This was triturated with EtOH (10 mL) to give thedesired product (4.550 g, 19.78 mmol, 36.1% yield) as an off-whitesolid.

2. 5-(2,5-Dimethyl-4-nitrophenoxy)pyrimidine

A solution of 1-bromo-2,5-dimethyl-4-nitrobenzene (3.53 g, 15.34 mmol),pyrimidin-5-ol (1.474 g, 15.34 mmol),2,2,6,6-tetramethylheptane-3,5-dione (0.141 g, 0.767 mmol), cesiumcarbonate (5.15 g, 15.80 mmol) and copper(I) chloride (0.410 g, 4.14mmol) in N-methyl-2-pyrrolidinone (15.34 mL) was heated in a sealedpressure tube at 130° C. and stirred overnight. The reaction was cooledto room temperature, diluted with EtOAc and washed with water (2×) andbrine, successively, dried over Na₂SO₄, filtered and concentrated invacuo. This was triturated with diethyl ether to give the first crop ofthe desired product (1.682 g) as a light tan solid. The filtrate wasconcentrated in vacuo, and the residue was purified by flashchromatography using an ISCO 80 g column eluting with 0-50%EtOAc/hexanes. Appropriate fractions were collected and concentrated invacuo to give the second crop of the desired product (0.3973 g) as anoff-white solid.

3.(E)-5-(2-Methyl-4-nitro-5-(2-(pyrrolidin-1-yl)vinyl)phenoxy)pyrimidine

A solution of 5-(2,5-dimethyl-4-nitrophenoxy)pyrimidine (0.7243 g, 2.95mmol), pyrrolidine (0.345 mL, 4.13 mmol) and DMF-DMA (0.551 mL, 4.13mmol) in DMF (3.0 mL) under nitrogen was heated at 115° C. After 45 min,the reaction was cooled to room temperature and concentrated in vacuo,followed by a short-path distillation. The crude residue was used in thesubsequent step.

4. 6-Methyl-5-(pyrimidin-5-yloxy)-1H-indole

A red, heterogeneous solution of(E)-5-(2-methyl-4-nitro-5-(2-(pyrrolidin-1-yl)vinyl)phenoxy)pyrimidine(0.963 g, 2.95 mmol) and 10% Pd/C (0.314 g, 0.295 mmol) in methanol(49.2 mL) was hydrogenated overnight. The reaction was flushed withnitrogen, filtered through a pad of CELITE®, and rinsed with MeOH. Thefiltrate was concentrated in vacuo to give a residue which was purifiedby flash chromatography using an ISCO 40 g column eluting with 0-5%MeOH/CH₂Cl₂. Appropriate fractions were collected and concentrated invacuo to the desired product (0.3082 g, 1.37 mmol, 46.4%) as a lightyellow solid.

5.3-(1-(2-Fluorophenyl)-2-nitroethyl)-6-methyl-5-(pyrimidin-5-yloxy)-1H-indole

6-Methyl-5-(pyrimidin-5-yloxy)-1H-indole (0.1783 g, 0.792 mmol) and(E)-1-fluoro-2-(2-nitrovinyl)benzene (0.159 g, 0.950 mmol) weredissolved in CH₂Cl₂, and the solution was concentrated in vacuo. Theresidue was heated at 130° C. for 4 hr, and the crude product waspurified by flash chromatography using an ISCO 40 g column eluting with0-5% MeOH/CH₂Cl₂. Appropriate fractions were collected and concentratedin vacuo to give the desired product (0.1644 g, 0.419 mmol, 52.9% yield)as a tan foam.

6.2-(2-Fluorophenyl)-2-(6-methyl-5-(pyrimidin-5-yloxy)-1H-indol-3-yl)ethanamine

To a spatula of Raney-Ni in a hydrogenation flask was added3-(1-(2-fluorophenyl)-2-nitroethyl)-6-methyl-5-(pyrimidin-5-yloxy)-1H-indole(0.284 g, 0.724 mmol) in methanol (12.06 mL). The reaction washydrogenated at 53 psi. After 3 hr, the vessel was evacuated and flushedwith nitrogen. The solution was filtered through a pad of CELITE® andrinsed with MeOH. The filtrate was concentrated in vacuo, dissolved inCH₂Cl₂, dried over Na₂SO₄, filtered and concentrated in vacuo to givethe desired product (0.2405 g, 0.664 mmol, 92% yield).

7. Ethyl4-(2-fluorophenyl)-7-methyl-6-(pyrimidin-5-yloxy)-9H-pyrido[3,4-b]indole-1-carboxylate

To a solution of2-(2-fluorophenyl)-2-(6-methyl-5-(pyrimidin-5-yloxy)-1H-indol-3-yl)ethanamine(0.262 g, 0.724 mmol) and 50% ethyl 2-oxoacetate in toluene (0.316 mL,1.593 mmol) in 1,4-dioxane (18.10 mL) under nitrogen was added 4 NHCl/1,4-dioxane (0.543 mL, 2.172 mmol). After stirring overnight, thereaction was concentrated in vacuo and dissolved in water. Saturatedaqueous NaHCO₃ was added until pH ˜12 by litmus paper. The solution wasextracted with EtOAc (2×). After separation of the layers, the organiclayer was dried over Na₂SO₄, filtered and concentrated in vacuo to givecrude product which was used in subsequent step. This was added to 10%Pd/C (0.770 g, 0.724 mmol) in toluene (10.34 mL), and the reaction wasrefluxed for 45 min. After cooling to room temperature, the reaction wasfiltered through a pad of CELITE® and rinsed with EtOAc. The filtratewas concentrated in vacuo to give a residue which was purified by flashchromatography using an ISCO 40 g column eluting with 0-2% MeOH/CH₂Cl₂.Appropriate fractions were collected and concentrated in vacuo to givethe desired product (0.0716 g, 0.162 mmol, 22.4% yield) as a tan solid.

8.4-(2-Fluorophenyl)-7-methyl-6-(pyrimidin-5-yloxy)-9H-pyrido[3,4-b]indole-1-carboxylicacid

A solution of ethyl4-(2-fluorophenyl)-7-methyl-6-(pyrimidin-5-yloxy)-9H-pyrido[3,4-b]indole-1-carboxylate(0.08 g, 0.181 mmol) and 1N aqueous NaOH (0.814 mL, 0.814 mmol) inmethanol (3.01 mL) was refluxed. After 1 hr, the reaction was cooled toroom temperature and concentrated in vacuo. Water was added, and thesolution was acidified to pH ˜4 by litmus paper. The precipitate wasfiltered, washed with water, and dried over Drierite to give the desiredproduct (0.0456 g, 0.110 mmol, 60.9% yield) as a yellow solid.

9.4-(2-Fluorophenyl)-7-methyl-6-(pyrimidin-5-yloxy)-9H-pyrido[3,4-b]indole-1-carboxamide

A sealed vial containing4-(2-fluorophenyl)-7-methyl-6-(pyrimidin-5-yloxy)-9H-pyrido[3,4-b]indole-1-carboxylicacid (0.0456 g, 0.110 mmol), ammonium chloride (0.024 g, 0.440 mmol),benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(BOP) (0.063 g, 0.143 mmol), DIPEA (0.092 mL, 0.528 mmol) andN-methylmorpholine (0.047 mL, 0.429 mmol) in DMF (0.8 mL) was stirred.After 1 hr, the reaction was diluted with MeOH (1 mL) and subjected toautoprep reverse phase HPLC purification. The appropriate fractions werecombined, basified with NaHCO₃ (solid), and concentrated in vacuo. Itwas extracted with CH₂Cl₂ (3×). The organic layers were combined, driedover Na₂SO₄, and concentrated in vacuo to give the desired product(0.0137 g, 0.033 mmol, 30.1% yield) as a light tan solid, LC/MS(M+H)=414.10; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 11.87 (br. S, 1 H), 8.98(s, 1H), 8.47 (s, 2H), 8.33 (br. S, 1H), 8.26 (s, 1H), 7.81 (s, 2H),7.59 (dd, J1=7.49, J2=1.39 Hz, 1H), 7.48-7.54 (m, 1H), 7.22-7.33 (m,2H), 6.72 (s, 1H), 2.35 (s, 3 H).

EXAMPLE 57-Amino-4-(2-fluorophenyl)-9H-pyrido[3,4-b]indole-1-carboxamide

1. Benzyl 1H-indol-6-ylcarbamate

A mixture of 1H-indol-6-amine (1.0 g, 7.57 mmol), benzylcarbonochloridate (1.421 mL, 9.46 mmol), and potassium carbonate (1.307g, 9.46 mmol) in tetrahydrofuran (50 mL) was stirred at room temperaturefor 16 hr. The mixture was diluted with ethyl acetate (150 mL) andinsoluble material was removed by filtration. The filtrate was washedsequentially with saturated NaHCO₃ solution (50 mL) and brine (50 mL).The organic solution was dried over anhydrous MgSO₄. The desired product(1.05 g, 3.94 mmol, 52.1% yield) was isolated as a white solid by ISCO(120 g silica gel, solid loading, 5-30% ethyl acetate/hexane).

2. Benzyl 3-(1-(2-fluorophenyl)-2-nitroethyl)-1H-indol-6-ylcarbamate

Benzyl 1H-indol-6-ylcarbamate (0.981 g, 3.68 mmol) and(E)-1-fluoro-2-(2-nitrovinyl)benzene (0.770 g, 4.60 mmol) were suspendedand well mixed in dichloromethane (15 mL). The suspension wasconcentrated under vacuum to dryness. The solid mixture was then heatedat 105° C. under nitrogen for 7 hr. The mixture was subjected to ISCO(120 g silica gel, solid loading, 20-45% ethyl acetate) to afford thedesired product (1.287 g, 2.97 mmol, 81% yield) as a white solid.

3. Benzyl 3-(2-amino-1-(2-fluorophenyl)ethyl)-1H-indol-6-ylcarbamate

A mixture of benzyl3-(1-(2-fluorophenyl)-2-nitroethyl)-1H-indol-6-ylcarbamate (0.600 g,1.384 mmol), zinc (1.358 g, 20.76 mmol), and ammonium chloride (1.111 g,20.76 mmol) in tetrahydrofuran (30 mL) and methanol (30.0 mL) wasstirred at room temperature for 2 hr. The insoluble material was removedby suction filtration through CELITE®. The filtrate was concentratedunder vacuum. The residue was diluted with ethyl acetate (100 mL),washed with 10% NaHCO₃ solution (25 mL) and brine (25 mL), and driedover anhydrous MgSO₄. Removal of solvent under vacuum provided thedesired product (0.586 g, 1.322 mmol, 95% yield) as a pale white solid.

4. Ethyl7-(benzyloxycarbonylamino)-4-(2-fluorophenyl)-9H-pyrido[3,4-b]indole-1-carboxylate

To a solution of benzyl3-(2-amino-1-(2-fluorophenyl)ethyl)-1H-indol-6-ylcarbamate (0.586 g,1.452 mmol) and ethyl 2-oxoacetate in toluene (50%) (0.576 mL, 2.90mmol) in 1,4-dioxane (15 mL) at room temperature was added hydrogenchloride in 1,4-dioxane (0.436 mL, 1.743 mmol). The mixture was stirredroom temperature for 16 hr. The volatiles were removed under vacuum. Theresidue was diluted with water (30 mL), basified with NaHCO₃ solution topH 10, and extracted with ethyl acetate (3×30 mL). The combined extractwas washed with brine (30 ml), dried over anhydrous MgSO₄, andconcentrated to dryness under vacuum. To the residue were added toluene(15 mL) and 10% Pd/C (0.2 g), and the mixture was heated at 110° C.under an ambient atmosphere for 3.5 hr. The solid phase was removed bysuction filtration. The filtrate was diluted with ethyl acetate (100ml), washed with brine (25 ml), and dried over anhydrous MgSO₄. Thedesired product (0.238 g, 0.492 mmol, 33.9% yield) was isolated as abeige solid by ISCO (40 g silica gel, solid loading, 20-40% ethylacetate/hexane).

5.7-(Benzyloxycarbonylamino)-4-(2-fluorophenyl)-9H-pyrido[3,4-b]indole-1-carboxylicacid

To a solution of ethyl7-(benzyloxycarbonylamino)-4-(2-fluorophenyl)-9H-pyrido[3,4-b]indole-1-carboxylate(0.238 g, 0.492 mmol) in tetrahydrofuran (12 mL) and methanol (4 mL) atroom temperature was added a solution of lithium hydroxide hydrate(0.083 g, 1.969 mmol) in water (1.8 mL). The mixture was stirred at roomtemperature for 1 hr, and then concentrated under vacuum. To the residuewas added water (5 ml), and the mixture was acidified to pH 5 with 1 NHCl. The precipitating product (0.214 g, 0.470 mmol, 95% yield) wascollected by suction filtration and dried over Drierite under vacuum.

6.4-(2-Fluorophenyl)-7-(isonicotinamido)-9H-pyrido[3,4-b]indole-1-carboxamide

A mixture of7-(benzyloxycarbonylamino)-4-(2-fluorophenyl)-9H-pyrido[3,4-b]indole-1-carboxylicacid (214 mg, 0.470 mmol), ammonium chloride (101 mg, 1.880 mmol),N,N-diisopropylamine (0.394 mL, 2.255 mmol), BOP (270 mg, 0.611 mmol),N-methylmorpholine (0.201 mL, 1.833 mmol) in DMF (2 mL) was stirred atrt for 1 hr. To the reaction solution was added water (20 mL), and theprecipitating product (213 mg, 0.422 mmol, 90% yield) was collected as abeige solid by suction filtration and dried over Drierite under vacuum.

7. 7-Amino-4-(2-fluorophenyl)-9H-pyrido[3,4-b]indole-1-carboxamide

A mixture of benzyl1-carbamoyl-4-(2-fluorophenyl)-9H-pyrido[3,4-b]indol-7-ylcarbamate (210mg, 0.416 mmol) and 10% Pd/C (45 mg, 0.042 mmol) in tetrahydrofuran (5mL) and methanol (15 mL) was stirred under H₂, provided with a H₂balloon, at rt for 1 hr. The catalyst was removed by suction filtrationthrough CELITE®. The filtrate was concentrated under vacuum. The residuewas diluted with CH₂Cl₂ (100 mL), washed with brine (30 mL), and driedover anhydrous MgSO₄. Removal of solvent under vacuum provided thedesired product,7-amino-4-(2-fluorophenyl)-9H-pyrido[3,4-b]indole-1-carboxamide (132 mg,0.375 mmol, 90% yield), as a tan solid. LCMS (M+H)⁺=321.10.

EXAMPLE 64-(2-Fluorophenyl)-7-(isonicotinamido)-9H-pyrido[3,4-b]indole-1-carboxamide

A mixture of7-amino-4-(2-fluorophenyl)-9H-pyrido[3,4-b]indole-1-carboxamide (25 mg,0.078 mmol), isonicotinic acid (11.53 mg, 0.094 mmol), BOP (49.7 mg,0.112 mmol), and N-methylmorpholine (0.037 mL, 0.337 mmol) in DMF (0.25mL) was stirred at room temperature for 1.5 hr. The mixture was dilutedwith MeOH (1.5 mL) and subjected to prep LC. reverse phase HPLCpurification. The correct fraction was concentrated under vacuum,basified with saturated NaHCO₃ solution to pH 9. The precipitatingproduct (10.8 mg, 0.025 mmol, 32.5% yield) was collected as a pale solidby suction filtration. LCMS (M+H)⁺=426.14. ¹H NMR (500 MHz, DMSO-d₆) δ:11.95 (s, 1H), 10.96 (s, 1H), 6.80 (m, 2H), 8.44 (s, 1H), 8.33 (s, 1H),8.27 (s, 1H), 7.89 (m, 2H), 7.79 (s, 1H), 7.71-7.67 (m, 2H), 7.54-7.48(m, 2H), 7.42 (dd, J1=8.6 Hz, J2=1.9 Hz, 1H), 7.28 (d, J=8.6 Hz, 1H).

EXAMPLE 74-(2-Fluorophenyl)-7-(tetrahydro-2H-pyran-4-ylamino)-9H-pyrido[3,4-b]indole-1-carboxamide

A mixture of7-amino-4-(2-fluorophenyl)-9H-pyrido[3,4-b]indole-1-carboxamide (30.0mg, 0.094 mmol), dihydro-2H-pyran-4(3H)-one (10.37 μL, 0.112 mmol), andsodium triacetoxyborohydride (39.7 mg, 0.187 mmol) in tetrahydrofuran (1mL) and dichloromethane (1 mL) was stirred at rt for 16 hr. Additionaldihydro-2H-pyran-4(3H)-one (10.37 μL, 0.112 mmol) and sodiumtriacetoxyborohydride (39.7 mg, 0.187 mmol) were added, and the mixturewas stirred at room temperature for another 8 hr. To the reactionmixture was added water (2 mL), and the resulting mixture was stirred atroom temperature for 20 min. It was diluted with ethyl acetate (50 mL),washed with saturated NaHCO₃ solution (15 mL) and brine (15 mL), anddried over anhydrous MgSO₄. Solvent was removed under vacuum, and theresidue was subjected to prep. reverse phase HPLC purification. Thecorrect fraction was concentrated under vacuum and basified withsaturated NaHCO₃ solution. The precipitating product (11.8 mg, 0.029mmol, 30.8% yield) was collected as a yellow solid by suction filtrationand dried at 50° C. under vacuum. LCMS (M+H)⁺=405.17. ¹H NMR (500 MHz,DMSO-d₆) δ: 11.30 (s, 1H), 8.23 (s, 1H), 8.11 (s, 1H), 7.70 (s, 1H),7.65-7.61 (m, 2H), 7.49-7.42 (m, 2H), 6.98 (d, J=8.0 Hz, 1H), 6.94 (s,1H), 6.46 (dd, J1=8.7 Hz, J2=1.5 Hz, 1H), 6.19 (br. s, 1H), 3.90 (m,2H), 3.47 (m, 1H), 3.43 (m, 2H), 1.94 (m, 2H), 1.44 (m, 2H).

EXAMPLE 84-(2-Fluorophenyl)-7-(methylsulfonamido)-9H-pyrido[3,4-b]indole-1-carboxamide

To a solution of7-amino-4-(2-fluorophenyl)-9H-pyrido[3,4-b]indole-1-carboxamide (25 mg,0.078 mmol) in dichloromethane (2 mL) at rt was sequentially addedmethanesulfonyl chloride (22.35 mg, 0.195 mmol) and pyridine (0.016 mL,0.195 mmol). The mixture was stirred at room temperature for 1 hr andthen at 50° C. in a closed vial for 30 min. The mixture wasconcentrated. The residue was diluted with MeOH (1.5 mL) and subjectedto prep. reverse phase HPLC purification. The correct fraction wasconcentrated under vacuum, basified with saturated NaHCO₃ solution to pH9, and extracted with ethyl acetate (3×30 mL). The combined extractswere washed with brine (25 mL) and dried over anhydrous MgSO₄. Removalof solvent under vacuum provided the desired product (4.81 mg, 0.012mmol, 15.00% yield) as a pale solid. LCMS (M+H)⁺=399.03. ¹H NMR (500MHz, DMSO-d₆) δ: 11.85 (s, 1H), 10.03 (s, 1H), 8.30 (s, 1H), 8.23 (s,1H), 7.77 (s, 1H), 7.75 (s, 1H), 7.67-7.63 (m, 2H), 7.50-7.43 (m, 2H),7.19 (d, J=7.7 Hz, 1H), 6.92 (dd, J1=8.8 Hz, J2=2.2 Hz, 1H), 3.02 (s,3H).

EXAMPLE 94-(3-(6-Chloro-1-oxoisoindolin-2-yl)-2-methylphenyl)-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indole-1-carboxamide

1. 6-(2-Methoxyethoxy)-1H-indole

A mixture of 1H-indol-6-ol (4.0 g, 30.0 mmol), 1-bromo-2-methoxyethane(3.53 mL, 37.6 mmol), and cesium carbonate (11.75 g, 36.1 mmol) in DMF(50 mL) was heated at 75° C. for 16 hr. DMF was removed under vacuumwith a oil pump. The residue was diluted with ethyl acetate (200 mL),washed sequentially with 1 N NaOH solution (50 mL), water (2×50 mL), andbrine (50 mL). The organic solution was dried over anhydrous MgSO₄ andconcentrated under vacuum. The desired product (4.68 g, 21.54 mmol,71.7% yield) was isolated as a white solid by ISCO (300 g silica gel,solid loading, 10-50% ethyl acetate/hexane).

2. 3-Amino-2-methylbenzonitrile

To a mixture of 2-methyl-3-nitrobenzonitrile (5.50 g, 33.9 mmol) andammonium chloride (25.4 g, 475 mmol) in tetrahydrofuran (100 mL) andmethanol (100 mL) at 0° C. was added zinc dust (31.1 g, 475 mmol) inportions. The mixture was stirred at room temperature for 2 hr. Theinsoluble material was removed by suction filtration through CELITE®,and the filtrate was concentrated under vacuum. The residue was dilutedwith water (50 mL) and extracted with CH₂Cl₂ (4×100 mL). The combinedextract was dried over anhydrous MgSO₄. Removal of solvent under vacuumprovided the desired product (4.19 g, 31.7 mmol, 93% yield) as a whitesolid.

3. Benzyl 3-cyano-2-methylphenylcarbamate

A mixture of 3-amino-2-methylbenzonitrile (4.32 g, 32.7 mmol), benzylcarbonochloridate (7.26 mL, 49.0 mmol), and potassium carbonate (6.78 g,79.0 mmol) in tetrahydrofuran (280 mL) was stirred at room temperaturefor 3 days. The insoluble material was removed by filtration, and thefiltrate was concentrated under vacuum. The residue was diluted withethyl acetate (250 mL), washed with 1N HCl solution (60 mL), water (60mL), and brine (60 mL). The organic solution was dried over anhydrousMgSO₄, and the solution was concentrated under vacuum to dryness. Theresidue was stirred with hexane (100 mL) at room temperature for 1 hr.The insoluble product (6.41 g, 24.07 mmol, 73.6% yield) was collected asa white solid by suction filtration.

4. Benzyl 3-formyl-2-methylphenylcarbamate

To a solution of benzyl 3-cyano-2-methylphenylcarbamate (6.41 g, 24.07mmol) in tetrahydrofuran (250 mL) at −78° C. was added DIBAL-H indichloromethane (96 mL, 96 mmol) over 1 hr. The mixture was stirred at−78° C. for 45 min and then at room temperature for 5 hr. It was pouredinto ice cold water (300 mL) and the resulting mixture was stirred atroom temperature for 30 min. The mixture was filtered through CELITE®,and the filtrate was concentrated to remove most of the THF. Theremaining aqueous solution was extracted with ethyl acetate (4×150 mL).The combined extract was dried over anhydrous MgSO₄. Removal of solventunder vacuum provided the desired product (5.65 g, 20.98 mmol, 87%yield) as a pale yellow solid.

5. (E)-Benzyl 2-methyl-3-(2-nitrovinyl)phenylcarbamate

A mixture of benzyl 3-formyl-2-methylphenylcarbamate (4.968 g, 18.45mmol), nitromethane (2.478 mL, 46.1 mmol), and ammonium acetate (3.56 g,46.1 mmol) in acetic acid (70 mL, 1223 mmol) was heated at 90° C. for4.5 hr. The acetic acid was removed under vacuum. To the residue wasadded water (100 mL), and the mixture was stirred at room temperaturefor 30 min. The insoluble material was collected with suctionfiltration. The filter cake was mixed with water (100 mL) and theaqueous mixture was adjusted to pH 9 with saturated NaHCO₃ solution andstirred at room temperature for 30 min. The insoluble product (4.13 g,88% purity, 13.22 mmol, 71.7% yield) was collected as a yellow solidwith suction filtration and dried over Drierite under vacuum.

6. Benzyl3-(1-(6-(2-methoxyethoxy)-1H-indol-3-yl)-2-nitroethyl)-2-methylphenylcarbamate

6-(2-Methoxyethoxy)-1H-indole (1.461 g, 88% purity, 6.72 mmol) and(E)-benzyl 2-methyl-3-(2-nitrovinyl)phenylcarbamate (1.75 g, 5.60 mmol)were dissolved in THF (50 mL). The solution was then concentrated undervacuum to dryness. The solid mixture was melted at 125° C. and heated atthis temperature for 16 hr. The mixture was subjected to ISCO (220 gsilica gel, solid loading, 25-65% ethyl acetate/hexane) to afford thedesired product (1.75 g, 3.48 mmol, 62% yield) as a beige solid.

7. Benzyl3-(2-amino-1-(6-(2-methoxyethoxy)-1H-indol-3-yl)ethyl)-2-methylphenylcarbamate

A mixture of benzyl3-(1-(6-(2-methoxyethoxy)-1H-indol-3-yl)-2-nitroethyl)-2-methylphenylcarbamate(1.75 g, 3.48 mmol), ammonium chloride (2.79 g, 52.1 mmol), and zincdust (3.41 g, 52.1 mmol) in tetrahydrofuran (35 mL) and methanol (35 mL)was stirred at room temperature for 4.5 hr. The mixture was diluted withethyl acetate (40 mL) and filtered through CELITE®. The filtrate wasconcentrated under vacuum, and the residue was diluted with water (40mL), basified with saturated NaHCO₃ solution, and extracted with ethylacetate (4×40 mL). The combined extract was washed with brine (40 mL)and dried over anhydrous MgSO₄. Removal of solvent under vacuum providedthe desired product (1.65 g, 3.48 mmol, 100% yield) as beige solid.

8. Ethyl4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indole-1-carboxylate

To a solution of benzyl3-(2-amino-1-(6-(2-methoxyethoxy)-1H-indol-3-yl)ethyl)-2-methylphenylcarbamate(0.780 g, 1.647 mmol) and ethyl 2-oxoacetate in toluene (50%) (0.653 mL,3.29 mmol) at room temperature was added hydrogen chloride in1,4-dioxane (4.0 M) (0.494 mL, 1.977 mmol). The mixture was stirred roomtemperature for 16 hr. The volatiles were removed under vacuum. Theresidue was diluted with water (50 mL), basified with NaHCO₃ solution topH 10, and extracted with ethyl acetate (4×50 mL). The combined extractwas washed with brine (40 ml), dried over anhydrous MgSO₄, andconcentrated to dryness under vacuum. To the residue were added p-xylene(60 mL) and 10% Pd/C (0.46 g), and the mixture was heated at 125° C.under an ambient atmosphere for 4.5 hr. The solid phase was removed bysuction filtration. The filtrate was diluted with ethyl acetate (120ml), washed with brine (40 ml), and dried over anhydrous MgSO₄. Thedesired product (0.399 g, 0.721 mmol, 43.8% yield) was isolated by ISCO(40 g silica gel, solid loading, 15-35% ethyl acetate/CH₂Cl₂).

9.4-(3-(Benzyloxycarbonylamino)-2-methylphenyl)-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indole-1-carboxylicacid

To a solution of ethyl4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indole-1-carboxylate(0.299 g, 0.540 mmol) in tetrahydrofuran (15 mL) and methanol (5 mL) atroom temperature was added a solution of lithium hydroxide hydrate(0.091 g, 2.160 mmol) in water (2 mL). The resulting mixture was stirredat room temperature for 1.5 hr, and then concentrated under vacuum toalmost dryness. To the residue was added water (8 mL), and the mixturewas neutralized with 1N HCl to pH 4-5. The insoluble product (0.237 g,0.451 mmol, 83% yield) was collected as a beige solid by suctionfiltration and dried over Drierite under vacuum.

10. Benzyl3-(1-carbamoyl-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indol-4-yl)-2-methylphenylcarbamate

A mixture of4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indole-1-carboxylicacid (0.237 g, 0.451 mmol), ammonium chloride (0.096 g, 1.804 mmol),N,N-diisopropylamine (0.378 mL, 2.165 mmol), BOP (0.259 g, 0.586 mmol),and N-methylmorpholine (0.193 mL, 1.759 mmol) in N,N-dimethylformamide(3 mL) was stirred at room temperature for 1.5 hr. To the reactionmixture was added water (30 mL), and the resulting mixture was stirredat room temperature for 30 min. The insoluble product (0.226 g, 0.431mmol, 96% yield) was collected as a beige solid by suction filtrationand dried over Drierite under vacuum.

11.4-(3-Amino-2-methylphenyl)-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indole-1-carboxamide

A mixture of benzyl3-(1-carbamoyl-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indol-4-yl)-2-methylphenylcarbamate(0.226 g, 0.431 mmol) and Pd/C (60 mg, 0.056 mmol) in tetrahydrofuran(12 mL) and methanol (18 mL) was stirred at room temperature under H₂,provided with a H₂ balloon, for 1.5 hr. The catalyst was removed bysuction filtration, and the filtrate was concentrated under vacuum. Theresidue was dissolved in ethyl acetate (80 mL) and dried over anhydrousMgSO₄. Removal of the solvent under vacuum provided the desired product(0.172 g, 0.441 mmol, 102% yield) as a beige solid.

12.2-((3-(1-Carbamoyl-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indol-4-yl)-2-methylphenylamino)methyl)-5-chlorobenzoicacid

A mixture of4-(3-amino-2-methylphenyl)-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indole-1-carboxamide(60.0 mg, 0.154 mmol), 5-chloro-2-formylbenzoic acid (70.9 mg, 0.384mmol), sodium triacetoxyborohydride (98 mg, 0.461 mmol), and acetic acid(0.018 mL, 0.307 mmol) in dichloroethane (3 mL) and tetrahydrofuran (2mL) was stirred at room temperature for 16 hr and then quenched withwater (3 mL). The resulting mixture was diluted with ethyl acetate (50mL) and washed with water (25 mL). The aqueous solution was extractedwith ethyl acetate (2×30 mL). The combined extract was washed with brine(25 mL) and dried over anhydrous MgSO₄. The organic solution wasconcentrated under vacuum to dryness. The residue was dissolved withminimum amount of DMF, diluted with MeOH (3 mL), divided into 2portions, and purified by prep. reverse phase HPLC. The correctfractions were combined, concentrated under vacuum, and lyophilized toafford the desired product (TFA salt) (38 mg, 0.056 mmol, 36.7% yield)as a white powder.

13.4-(3-(6-Chloro-1-oxoisoindolin-2-yl)-2-methylphenyl)-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indole-1-carboxamide

A mixture of2-((3-(1-carbamoyl-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indol-4-yl)-2-methylphenylamino)methyl)-5-chlorobenzoicacid, TFA (38 mg, 0.056 mmol), N,N-diisopropylamine (0.015 mL, 0.085mmol), BOP (32.5 mg, 0.073 mmol), and N-methylmorpholine (0.024 mL,0.220 mmol) in DMF (4 mL) was heated at 45° C. for 1 hr. The mixture wasdiluted with ethyl acetate (60 mL), washed sequentially with water (3×25mL) and brine (25 mL), and dried over anhydrous MgSO₄. After the solventwas removed under vacuum, the residue was purified by prep. Reversephase HPLC. The correct fraction was concentrated under vacuum, basifiedwith saturated NaHCO₃ solution, and extracted with CH₂Cl₂ (3×30 mL). Thecombined extract was washed with brine (30 mL) and dried over anhydrousMgSO₄. Removal of solvent under vacuum provided the desired product(21.7 mg, 0.039 mmol, 68.2% yield) as a yellow solid. LCMS(M+H)⁺=541.33. ¹H NMR (500 MHz, DMSO-d₆) δ: 11.66 (s, 1H), 8.30 (s, 1H),8.20 (s, 1H), 7.82 (s, 1H), 7.77-7.73 (m, 3H), 7.67 (m, 1H), 7.54 (m,1H), 7.45 (m, 1H), 7.36 (d, J=2.2 Hz, 1H), 7.14 (d, J=8.9 Hz, 1H), 6.71(dd, J1=8.7 Hz, J2=2.4 Hz, 1H), 5.04 (d, J=17.5 Hz, 1H), 4.95 (d, J=17.5Hz, 1H), 4.16 (m, 2H), 3.72 (m, 2H), 3.34 (s, 3H), 1.87 (s, 3H).

EXAMPLE 107-(2-Methoxyethoxy)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide

A mixture of4-(3-amino-2-methylphenyl)-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indole-1-carboxamide(330 mg, 0.845 mmol), 1H-benzo[d][1,3]oxazine-2,4-dione (345 mg, 2.113mmol), trimethoxymethane (0.926 mL, 8.45 mmol), andtris(nitrooxy)lanthanum, 6H₂O (110 mg, 0.254 mmol) in tetrahydrofuran(Volume: 2 mL) was heated at 95° C. in a sealed vial for 20 hr. Themixture was diluted with ethyl acetate (100 mL), washed with water (30mL), 1 N NaOH solution (30 mL), and brine (30 mL). The organic solutionwas dried over anhydrous MgSO₄ and concentrated under vacuum. Theresidue was subjected to prep. reverse phase HPLC purification. Thecorrect fractions were concentrated under vacuum, basified withsaturated NaHCO₃ solution, and extracted with ethyl acetate (3×35 mL).The combined extract was washed with brine (30 mL) and dried overanhydrous MgSO₄. Removal of solvent under vacuum provided the desiredproduct (188 mg, 0.362 mmol, 42.8% yield) as a yellow solid. The productis mixture of two atropisomers at rt. LCMS (M+H)⁺=520.29. ¹H NMR (500MHz, DMSO-d₆) (recognizable peaks for the major atropisomer) δ: 11.68(s, 1H), 8.44 (s, 1H), 8.21 (s, 1H), 7.36 (s, 1H), 7.25 (d, J=8.9 Hz),4.17 (m, 2H), 3.73 (m, 2H), 3.35 (s, 3H), 1.81 (s, 3H).

EXAMPLE 117-(2-Hydroxyethoxy)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide

To a solution of7-(2-methoxyethoxy)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide(101 mg, 0.194 mmol) in dichloromethane (5 mL) at 0° C. was addedtribromoborane in dichloromethane (0.622 mL, 0.622 mmol) over 5 min. Theresulting heterogeneous mixture was stirred at room temperature for 1.5hr. The reaction was quenched with ice water (15 mL). The mixture wasbasified with 1 N NaOH solution to pH 10 and extracted with ethylacetate (3×40 mL). The combined extract was washed with brine (30 mL)and dried over anhydrous MgSO₄. After the solvent was removed undervacuum, the residue was purified by reverse phase HPLC. The correctfraction was concentrated under vacuum, basified with saturated NaHCO₃solution, and extracted with ethyl acetate (3×30 mL). The combinedextract was washed with brine (30 mL) and dried over anhydrous MgSO₄.Removal of solvent under vacuum provided the desired product (44.0 mg,0.084 mmol, 43.3% yield) as a yellow solid. The product is mixture oftwo atropisomers at rt. LCMS (M+H)⁺=506.23. ¹H NMR (500 MHz, DMSO-d₆)(recognizable peaks for the major atropisomer) δ: 11.67 (s, 1H), 8.44(s, 1H), 8.21 (s, 1H), 7.37 (s, 1H), 4.07 (m, 2H), 3.78 (m, 2H), 1.81(s, 3H).

EXAMPLE 127-Hydroxy-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide

A mixture of7-(2-methoxyethoxy)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide(70 mg, 0.135 mmol) and aluminum triiodide (137 mg, 0.337 mmol) inacetonitrile (6 mL) was heated at reflux for 4 hr. Upon cooling to roomtemperature, the reaction was quenched with ice water (20 mL). Themixture was extracted with ethyl acetate (3×30 mL). The combined extractwas with brine (25 mL) and dried over anhydrous MgSO₄. After the solventwas removed under vacuum, the residue was purified by reverse phaseHPLC. The correct fractions were concentrated under vacuum, basifiedwith saturated NaHCO₃ solution, and extracted with ethyl acetate (3×30mL). The combined extract was washed with brine (30 mL) and dried overanhydrous MgSO₄. Removal of solvent under vacuum provided the desiredproduct (12.9 mg, 0.026 mmol, 19.54% yield) as a yellow solid. LCMS(M+H)⁺=462.23. ¹H NMR (500 MHz, DMSO-d₆) (recognizable peaks for themajor atropisomer) δ: 11.56 (s, 1H), 9.84 (s, 1H), 8.16 (s, 1H), 7.19(s, 1H), 7.16 (d, J=8.6 Hz, 1H), 1.81 (s, 3H).

EXAMPLE 137-(2-Methoxyethoxy)-4-(2-methyl-3-(4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide

A mixture of4-(3-amino-2-methylphenyl)-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indole-1-carboxamide(60 mg, 0.154 mmol), 3-aminopicolinic acid (53.1 mg, 0.384 mmol),trimethoxymethane (0.151 mL, 1.383 mmol), and tris(nitrooxy)lanthanum,6H₂O (19.96 mg, 0.046 mmol) in tetrahydrofuran (0.2 mL) was heated at95° C. in a sealed vial for 16 hr. The mixture remained heterogeneousand very little (<5%) of the desired product was formed. DMF (0.5 mL)was added to the reaction mixture. Also added were additional3-aminopicolinic acid (26.5 mg, 0.192 mmol) and tris(nitrooxy)lanthanum,6H₂O (10 mg, 0.023 mmol). The mixture was heated at 90° C. for two days.It was diluted with ethyl acetate (100 mL) and washed sequentially withwater (25 mL), 1 N NaOH solution (25 mL), water (25 ml), and brine (25mL). The organic solution was dried over anhydrous MgSO₄ andconcentrated under vacuum. The residue was purified by reverse phaseHPLC. The correct fractions were concentrated under vacuum, basifiedwith saturated NaHCO₃ solution, and extracted with ethyl acetate (3×30mL). The combined extract was washed with brine (30 mL) and dried overanhydrous MgSO₄. Removal of solvent under vacuum provided the desiredproduct (7.1 mg, 0.013 mmol, 8.51% yield) as a yellow solid. LCMS(M+H)⁺=521.03. ¹H NMR (500 MHz, DMSO-d₆) (recognizable peaks for themajor atropisomer) δ: 11.68 (s, 1H), 8.89 (s, 1H), 8.53 (s, 1H), 8.29(s, 1H), 8.21 (s, 1H), 7.91 (m, 1H), 7.37 (s, 1H), 4.18 (m, 2H), 3.73(m, 2H), 3.35 (s, 3H), 1.84 (s, 3H).

EXAMPLE 147-(2-Hydroxypropoxy)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide

1.4-(2-Methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-7-(2-oxoethoxy)-9H-pyrido[3,4-b]indole-1-carboxamide

To a solution of7-(2-hydroxyethoxy)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide(152 mg, 0.301 mmol) in dichloromethane (10 mL) and tetrahydrofuran(10.00 mL) at room temperature was added Dess-Martin periodinane (191mg, 0.451 mmol) in one portion. The mixture was stirred at roomtemperature for 16 hr. To the mixture was added saturated NaHCO₃solution (10 mL) and water (10 mL). The mixture was stirred at roomtemperature for 20 min and extracted with ethyl acetate (3×40 mL). Thecombined extract was washed with brine (30 mL) and dried over anhydrousMgSO₄. Removal of solvent under vacuum provided the desired product (178mg, 0.354 mmol, 118% yield) as a beige solid.

2.7-(2-Hydroxypropoxy)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide

To a solution of4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-7-(2-oxoethoxy)-9H-pyrido[3,4-b]indole-1-carboxamide(178 mg, 85% purity, 0.300 mmol) in tetrahydrofuran (10 mL) at 0° C. wasadded methylmagnesium bromide (0.707 mL, 2.121 mmol). The mixture wasstirred at rt for 20 min. Additional methylmagnesium bromide (0.50 mL,1.50 mmol) was added. The mixture was stirred at room temperature foranother 20 min and then the reaction was quenched with water (20 mL).The resulting mixture was extracted with ethyl acetate (3×40 mL). Thecombined extract was washed with brine (30 mL) and dried over anhydrousMgSO₄. After solvent was removed under vacuum, the residue was purifiedby reverse phase HPLC. The correct fractions were combined andconcentrated under vacuum, basified with saturated NaHCO₃ solution, andextracted with ethyl acetate (3×35 mL). The combined extract was washedwith brine (30 mL) and dried over anhydrous MgSO₄. Removal of solventunder vacuum provided the desired product (7.6 mg, 0.014 mmol, 4.9%yield) as a yellow solid. LCMS (M+H)⁺=520.21. ¹H NMR (500 MHz, DMSO-d₆)(recognizable peaks for the major atropisomer) δ: 11.68 (s, 1H), 8.44(s, 1H), 8.21 (s, 1H), 7.36 (s, 1H), 4.01 (m, 1H), 3.92-3.84 (m, 2H),1.81 (s, 3H).

EXAMPLE 154-(3-(6-Fluoro-1-oxoisoindolin-2-yl)-2-methylphenyl)-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indole-1-carboxamide

1. 6-Fluoroisobenzofuran-1(3H)-one

A mixture of methyl 2-(bromomethyl)-5-fluorobenzoate (0.750 g, 3.04mmol) and calcium carbonate (1.823 g, 18.21 mmol) in 1,4-dioxane (30 mL)and water (30.0 mL) was heated at reflux for 2.5 hr. The insolublematerial was removed by filtration. The filtrate was concentrated undervacuum and then extracted with CH₂Cl₂ (4×30 mL). The combined extractwas dried over anhydrous MgSO₄. Removal of solvent under vacuum providedthe desired product (0.423 g, 2.78 mmol, 92% yield) as a white solid.

2. 5-Fluoro-2-(hydroxymethyl)benzoic acid

To a solution of 6-fluoroisobenzofuran-1(3H)-one (0.549 g, 3.61 mmol) inmethanol (12 mL) and water (3 mL) at room temperature was addedpotassium hydroxide (0.350 g, 6.24 mmol). The mixture was heated atreflux for 1.5 hr. The mixture was concentrated under vacuum to a volumeof about 3 mL. The residue was acidified with 1 M KHSO₄ solution to pH3-4. The insoluble material (inorganic salt) was removed by suctionfiltration and the filtrate was extracted with ethyl acetate (5×30 mL).The combined extract was dried over anhydrous MgSO₄. Removal of solventunder vacuum provided the desired product (0.479 g, 2.82 mmol, 78%yield) as a white solid.

3. 5-Fluoro-2-formylbenzoic acid

A mixture of 5-fluoro-2-(hydroxymethyl)benzoic acid (0.518 g, 3.04 mmol)and manganese(IV) oxide (3.71 g, 42.6 mmol) in tetrahydrofuran (25 mL)was stirred at room temperature for 16 hr. The insoluble material wasremoved by filtration through CELITE®. The filtrate was concentratedunder vacuum to dryness. The residue was dissolved in CH₂Cl₂ (100 mL)and dried over anhydrous MgSO₄. Removal of solvent under vacuum providedthe desired product (0.211 g, 1.255 mmol, 41.2% yield) as a white solid.

4.2-((3-(1-Carbamoyl-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indol-4-yl)-2-methylphenylamino)methyl)-5-fluorobenzoicacid

A mixture of4-(3-amino-2-methylphenyl)-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indole-1-carboxamide(60.0 mg, 0.154 mmol), 5-fluoro-2-formylbenzoic acid (64.6 mg, 0.384mmol), sodium triacetoxyborohydride (98 mg, 0.461 mmol), and acetic acid(0.022 mL, 0.384 mmol) in dichloroethane (3 mL) and tetrahydrofuran (2mL) was stirred at room temperature for 16 hr and then quenched withwater (3 mL). The resulting mixture was diluted with ethyl acetate (50mL) and washed with water (25 mL). The aqueous solution was extractedwith ethyl acetate (2×30 mL). The combined extract was washed with brine(25 mL) and dried over anhydrous MgSO₄. The organic solution wasconcentrated under vacuum to dryness. The residue was dissolved withminimum amount of DMF, diluted with MeOH (3 mL), divided into 2portions, and purified by reverse phase HPLC. The correct fractions werecombined, concentrated under vacuum, and lyophilized to afford thedesired product (TFA salt) (31.6 mg, 0.048 mmol, 31.3% yield) as a whitepowder.

5.4-(3-(6-Fluoro-1-oxoisoindolin-2-yl)-2-methylphenyl)-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indole-1-carboxamide

A mixture of2-((3-(1-carbamoyl-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indol-4-yl)-2-methylphenylamino)methyl)-5-fluorobenzoicacid, TFA (31.6 mg, 0.048 mmol), N,N-diisopropylamine (0.013 mL, 0.072mmol), BOP (27.7 mg, 0.063 mmol), and N-methylmorpholine (0.021 mL,0.188 mmol) in DMF (4 mL) was heated at 45° C. for 1 hr. The mixture wasdiluted with ethyl acetate (60 mL), washed sequentially with water (3×25mL) and brine (25 mL), and dried over anhydrous MgSO₄. After the solventwas removed under vacuum, the residue was purified by reverse phaseHPLC. The correct fraction was concentrated under vacuum, basified withsaturated NaHCO₃ solution, and extracted with ethyl acetate (3×30 mL).The combined extract was washed with brine (30 mL) and dried overanhydrous MgSO₄. Removal of solvent under vacuum provided the desiredproduct (13.3 mg, 0.025 mmol, 51.0% yield) as a yellow solid. LCMS(M+H)⁺=525.09. ¹H NMR (500 MHz, DMSO-d₆) δ: 11.72 (s, 1H), 8.37 (s, 1H),8.25 (s, 1H), 7.82-7.79 (m, 2H), 7.72 (d, J=7.8 Hz, 1H), 7.65 (m, 1H),7.63-7.58 (m, 2H), 7.50 (d, J=6.9 Hz, 1H), 7.41 (d, J=2.2 Hz, 1H), 7.20(d, J=8.6 Hz, 1H), 6.76 (dd, J1=8.9 Hz, J2=2.2 Hz, 1H), 5.08 (d, J=17.2Hz, 1H), 4.98 (d, J=17.2 Hz, 1H), 4.21 (m, 2H), 3.77 (m, 2H), 3.40 (s,3H), 1.92 (s, 3H).

EXAMPLE 167-(2-Methoxyethoxy)-4-(2-methyl-3-(quinazolin-4-ylamino)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide

A mixture of4-(3-amino-2-methylphenyl)-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indole-1-carboxamide(51 mg, 0.131 mmol), and 4-chloroquinazoline (47.3 mg, 0.287 mmol) in2-Propanol (5 mL) was heated at 115° C. under microwave for 30 min. Themixture was diluted with ethyl acetate (80 mL), washed with saturatedNaHCO₃ solution (20 mL) and brine (20 mL), and dried over anhydrousMgSO₄. The solvent was removed under vacuum, and the residue waspurified by reverse phase HPLC. The correct fractions were concentratedunder vacuum, basified with saturated NaHCO₃ solution, and extractedwith ethyl acetate (3×30 mL). The combined extract was washed with brine(30 mL) and dried over anhydrous MgSO₄. Removal of solvent under vacuumprovided the desired product (18.0 mg, 0.033 mmol, 25.5% yield) as ayellow solid. LCMS (M+H)⁺=519.30. ¹H NMR (500 MHz, DMSO-d₆) δ: 11.65 (s,1H), 10.17 (s, 1H), 8.61 (s, 1H), 8.55 (d, J=8.0 Hz, 1H), 8.29 (s, 1H),8.19 (s, 1H), 7.89 (m, 1H), 7.80 (d, J=8.3 Hz, 1H), 7.75 (s, 1H), 7.66(m, 1H), 7.55-7.49 (m, 2H), 7.38-7.36 (m, 2H), 7.33 (d, J=8.9 Hz, 1H),6.80 (dd, J1=8.7 Hz, J2=2.4 Hz, 1H), 4.17 (m, 2H), 3.73 (m, 2H), 3.34(s, 3H), 1.87 (s, 3H).

EXAMPLE 174-(2-Methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-7-morpholino-9H-pyrido[3,4-b]indole-1-carboxamide

1. Benzyl2-methyl-3-(1-(6-morpholino-1H-indol-3-yl)-2-nitroethyl)phenylcarbamate

A solution of 4-(1H-indol-6-yl)morpholine (1.1132 g, 5.50 mmol) and(E)-benzyl 2-methyl-3-(2-nitrovinyl)phenylcarbamate (2.58 g, 8.26 mmol)in THF (50 mL) was concentrated in vacuo. The residue was melted at 137°C. and stirred overnight. After cooling to room temperature, the crudeproduct was purified by flash chromatography using an ISCO 330 g column(solid loading) eluting with 40-80% EtOAc/hexanes to give the desiredproduct (0.9544 g, 1.855 mmol, 33.7% yield) as a light brown solid.

2. Benzyl3-(2-amino-1-(6-morpholino-1H-indol-3-yl)ethyl)-2-methylphenylcarbamate

A heterogeneous solution of benzyl2-methyl-3-(1-(6-morpholino-1H-indol-3-yl)-2-nitroethyl)phenylcarbamate(1.8743 g, 3.64 mmol), ammonium chloride (2.92 g, 54.6 mmol) and zinc(3.57 g, 54.6 mmol) in THF (Ratio: 1.000, Volume: 79 ml) and methanol(Ratio: 1.000, Volume: 79 ml) was stirred under nitrogen for 2.5 hr.EtOAc (60 mL) was added, and the solution was filtered through a pad ofCELITE®. The filtrate was concentrated in vacuo; the residue wasdissolved in water (50 mL) and EtOAc (75 mL). After separation of thelayers, the aqueous layer was extracted with EtOAc (2×75 mL). Theorganic layers were combined, dried over MgSO₄, and concentrated invacuo to give the desired product (1.4934 g, 3.08 mmol, 85% yield) as atan solid.

3. Ethyl4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-7-morpholino-9H-pyrido[3,4-b]indole-1-carboxylate

To a homogeneous solution of benzyl3-(2-amino-1-(6-morpholino-1H-indol-3-yl)ethyl)-2-methylphenylcarbamate(1.4934 g, 3.08 mmol) in dioxane (154 ml) were added 50% ethyl2-oxoacetate/toluene (1.222 ml, 6.16 mmol) and 4N HCl/dioxane (1.541 ml,6.16 mmol) under nitrogen. The reaction was stirred overnight. More 50%ethyl 2-oxoacetate/toluene (1.222 ml, 6.16 mmol) was added, and thereaction was stirred overnight. The reaction was concentrated in vacuo,dissolved in EtOAc (100 mL) and washed with water (25 mL) and brine (25mL) successively, dried over MgSO₄, and concentrated in vacuo to give acrude product, which was used in the subsequent step. To this crude wereadded 10% Pd/C (0.819 g, 0.770 mmol) and toluene (77 ml), and themixture was refluxed overnight. The reaction was cooled to roomtemperature, diluted with EtOAc (200 mL), and filtered through a pad ofCELITE®. The filtrate was washed with water (75 mL) and brine (75 mL),dried over MgSO₄, and concentrated in vacuo. The residue was purified byflash chromatography using an ISCO 120 g column eluting with 15-70%EtOAc/CH₂Cl₂ to give the desired product (0.354 g, 0.627 mmol, 20.4%yield) as a tan solid.

4.4-(3-(Benzyloxycarbonylamino)-2-methylphenyl)-7-morpholino-9H-pyrido[3,4-b]indole-1-carboxylicacid

To a solution of ethyl4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-7-morpholino-9H-pyrido[3,4-b]indole-1-carboxylate(0.3539 g, 0.627 mmol) in THF (17.4 mL) and MeOH (5.8 mL) was added asolution of lithium hydroxide hydrate (0.105 g, 2.507 mmol) in water (3mL). After 1 hr, the reaction was concentrated in vacuo. Water (12 mL)was added, and the solution was acidified with aqueous 1N HCl to pH 5-6by litmus paper. The precipitate was filtered, washed with water, driedover Drierite to give the desired product (0.286 g, 0.533 mmol, 85%yield) as an orange solid.

5. Benzyl3-(1-carbamoyl-7-morpholino-9H-pyrido[3,4-b]indol-4-yl)-2-methylphenylcarbamate

A homogeneous, burgundy solution of4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-7-morpholino-9H-pyrido[3,4-b]indole-1-carboxylic acid (0.2860 g, 0.533 mmol), ammonium chloride(0.114 g, 2.132 mmol), BOP (0.306 g, 0.693 mmol), DIPEA (0.447 ml, 2.56mmol) and N-methylmorpholine (0.229 ml, 2.079 mmol) in DMF (Volume: 3.33ml) was stirred. After 1 hr, water (35 mL) was added and the mixture wasstirred at room temperature for 30 min. The precipitate was filtered,washed with water, dried over Drierite to give the desired product(0.274 g, 0.511 mmol, 96% yield) as a tan solid.

6.4-(3-Amino-2-methylphenyl)-7-morpholino-9H-pyrido[3,4-b]indole-1-carboxamide

A solution of benzyl3-(1-carbamoyl-7-morpholino-9H-pyrido[3,4-b]indol-4-yl)-2-methylphenylcarbamate(0.2735 g, 0.511 mmol) and 10% Pd/C (0.109 g, 0.102 mmol) in THF (12.8mL) and MeOH (19.2 mL) was hydrogenated. After 1.5 hr, the reaction wasflushed with nitrogen and filtered through a wad of CELITE®. Thefiltrate was concentrated in vacuo, dissolved in CH₂Cl₂, dried overMgSO₄, and concentrated in vacuo to give the desired product (0.196 g,0.450 mmol, 88% yield) as a tan solid.

7.4-(2-Methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-7-morpholino-9H-pyrido[3,4-b]indole-1-carboxamide

A burgundy solution of4-(3-amino-2-methylphenyl)-7-morpholino-9H-pyrido[3,4-b]indole-1-carboxamide(0.0612 g, 0.140 mmol), 1H-benzo[d][1,3]oxazine-2,4-dione (0.057 g,0.351 mmol), trimethoxymethane (0.154 ml, 1.402 mmol) and lanthanumnitrate hexahydrate (0.018 g, 0.042 mmol) in THF (0.334 mL) in a sealedvial was stirred overnight at 95° C. The reaction was cooled to roomtemperature and concentrated in vacuo. The residue was dissolved in DMSO(0.2 mL) and MeOH (1.6 mL), and subjected to autoprep reverse phaseHPLC. The appropriate fractions were collected, basified with NaHCO₃(solid), and concentrated in vacuo. The residue was extracted withCH₂Cl₂ (3×). The combine extract was dried over Na₂SO₄ and concentratedin vacuo to give the desired product (0.0135 g, 0.024 mmol, 17.1% yield)as a tan solid. LC/MS (M+H)=531.29; ¹H NMR (500 MHz, DMSO-d₆)(recognizable peaks for major atropoisomer) δ ppm 11.48 (1 H, s), 8.42(1 H, s), 8.21-8.28 (2 H, m), 8.15 (1 H, s), 7.88-7.94 (1 H, m),7.76-7.81 (1 H, m), 7.69-7.74 (1 H, m), 7.53-7.69 (4 H, m), 7.27 (1 H,d, J=2.22 Hz), 6.79-6.86 (1 H, m), 3.74-3.81 (4 H, m), 3.16-3.23 (4 H,m), 1.81 (3 H, s).

EXAMPLE 184-(3-(5-Fluoroisoindoline-2-carboxamido)-2-methylphenyl)-7-(tetrahydrofuran-3-yloxy)-9H-pyrido[3,4-b]indole-1-carboxamide

1. 6-(Tetrahydrofuran-3-yloxy)-1H-indole

To a mixture of 1H-indol-6-ol (2.00 g, 15.02 mmol), tetrahydrofuran-3-ol(1.46 mL, 18.0 mmol), and triphenylphosphine (4.33 g, 16.52 mmol) indichloromethane (80 mL) at 0° C. was added diisopropyldiazene-1,2-dicarboxylate (3.49 mL, 18.03 mmol) over 10 min. The mixturewas stirred at room temperature for 16 hr. The starting indole anddesired product were detected in a ratio of 3:2. The dark mixture wasdiluted with CH₂Cl₂ (80 mL), washed with 1N NaOH (50 mL), water (50 mL),and brine (50 mL). The organic solution was dried over anhydrous MgSO₄.The desired product (0.642 g, 3.16 mmol, 21.03% yield) was isolated asviscous oil by ISCO (300 g silica gel, solid loading, 10-50% ethylacetate/hexane).

2. Benzyl2-methyl-3-(2-nitro-1-(6-(tetrahydrofuran-3-yloxy)-1H-indol-3-yl)ethyl)phenylcarbamate

6-(Tetrahydrofuran-3-yloxy)-1H-indole (0.632 g, 3.11 mmol) and(E)-benzyl 2-methyl-3-(2-nitrovinyl)phenylcarbamate (0.800 g, 2.56 mmol)were dissolved in THF (50 mL). The solution was then concentrated undervacuum to dryness. The solid mixture was melted at 130° C. and heated atthis temperature for 6 hr. The mixture was subjected to ISCO (120 gsilica gel, solid loading, 25-65% ethyl acetate/hexane) to afford thedesired product (0.612 g, 1.187 mmol, 46.3% yield) as a beige solid.

3. Benzyl3-(2-amino-1-(6-(tetrahydrofuran-3-yloxy)-1H-indol-3-yl)ethyl)-2-methylphenylcarbamate

A mixture of benzyl2-methyl-3-(2-nitro-1-(6-(tetrahydrofuran-3-yloxy)-1H-indol-3-yl)ethyl)phenylcarbamate(0.720 g, 1.397 mmol), ammonium chloride (1.121 g, 20.95 mmol), and zincdust (1.370 g, 20.95 mmol) in tetrahydrofuran (35 mL) and methanol (35mL) was stirred at room temperature for 4.5 hr. The mixture was dilutedwith ethyl acetate (40 mL) and filtered through CELITE®. The filtratewas concentrated under vacuum, and the residue was diluted with water(40 mL), basified with saturated NaHCO₃ solution, and extracted withethyl acetate (4×40 mL). The combined extract was washed with brine (40mL) and dried over anhydrous MgSO₄. Removal of solvent under vacuumprovided the desired product (0.678 g, 1.396 mmol, 100% yield) as abeige solid.

4. Ethyl4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-7-(tetrahydrofuran-3-yloxy)-9H-pyrido[3,4-b]indole-1-carboxylate

To a solution of benzyl3-(2-amino-1-(6-(tetrahydrofuran-3-yloxy)-1H-indol-3-yl)ethyl)-2-methylphenylcarbamate(0.678 g, 1.396 mmol) and ethyl 2-oxoacetate in toluene (50%) (0.554 mL,2.79 mmol) at room temperature was added hydrogen chloride in1,4-dioxane (4.0 M) (0.419 mL, 1.676 mmol). The mixture was stirred roomtemperature for 16 hr. The volatiles were removed under vacuum. Theresidue was diluted with water (50 mL), basified with NaHCO₃ solution topH 10, and extracted with ethyl acetate (4×50 mL). The combined extractwas washed with brine (40 ml), dried over anhydrous MgSO₄, andconcentrated to dryness under vacuum. To the residue were added p-xylene(60 mL) and 10% Pd/C (0.46 g), and the mixture was heated at 125° C.under an ambient atmosphere for 4.5 hr. The solid phase was removed bysuction filtration. The filtrate was diluted with ethyl acetate (120ml), washed with brine (40 ml), and dried over anhydrous MgSO₄. Thedesired product (0.240 g, 0.424 mmol, 30.4% yield) was isolated by ISCO(40 g silica gel, solid loading, 15-35% ethyl acetate/CH₂Cl₂).

5.4-(3-(Benzyloxycarbonylamino)-2-methylphenyl)-7-(tetrahydrofuran-3-yloxy)-9H-pyrido[3,4-b]indole-1-carboxylicacid

To a solution of ethyl4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-7-(tetrahydrofuran-3-yloxy)-9H-pyrido[3,4-b]indole-1-carboxylate(0.240 g, 0.424 mmol) in tetrahydrofuran (12 mL) and methanol (4 mL) atroom temperature was added a solution of lithium hydroxide hydrate(0.071 g, 1.696 mmol) in water (2 mL). The resulting mixture was stirredat room temperature for 1.5 hr, and then concentrated under vacuum toalmost dryness. To the residue was added water (8 mL), and the mixturewas neutralized with 1N HCl to pH 4-5. The insoluble product (0.195 g,0.363 mmol, 86% yield) was collected as a beige solid by suctionfiltration and dried over Drierite under vacuum.

6. Benzyl3-(1-carbamoyl-7-(tetrahydrofuran-3-yloxy)-9H-pyrido[3,4-b]indol-4-yl)-2-methylphenylcarbamate

A mixture of4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-7-(tetrahydrofuran-3-yloxy)-9H-pyrido[3,4-b]indole-1-carboxylicacid (0.195 g, 0.363 mmol), ammonium chloride (0.078 g, 1.451 mmol),N,N-diisopropylethylamine (0.304 mL, 1.741 mmol), BOP (0.209 g, 0.472mmol), and N-methylmorpholine (0.156 mL, 1.415 mmol) inN,N-dimethylformamide (3 mL) was stirred at room temperature for 1.5 hr.To the reaction mixture was added water (30 mL), and the resultingmixture was stirred at room temperature for 30 min. The insolubleproduct (0.189 g, 0.352 mmol, 97% yield) was collected as a beige solidby suction filtration and dried over Drierite under vacuum.

7.4-(3-Amino-2-methylphenyl)-7-(tetrahydrofuran-3-yloxy)-9H-pyrido[3,4b]indole-1-carboxamide

A mixture of benzyl3-(1-carbamoyl-7-(tetrahydrofuran-3-yloxy)-9H-pyrido[3,4-b]indol-4-yl)-2-methylphenylcarbamate(189 mg, 0.352 mmol) and Pd/C (50 mg, 0.047 mmol) in tetrahydrofuran (10mL) and methanol (15 mL) was stirred at room temperature under H_(z),provided with H₂ balloon, for 1.5 hr. The catalyst was removed bysuction filtration, and the filtrate was concentrated under vacuum todryness to afford the desired product (164 mg, 0.350 mmol, 99% yield) asa beige solid.

8.4-(3-(5-Fluoroisoindoline-2-carboxamido)-2-methylphenyl)-7-(tetrahydrofuran-3-yloxy)-9H-pyrido[3,4-b]indole-1-carboxamide

To a heterogeneous mixture of4-(3-amino-2-methylphenyl)-7-(tetrahydrofuran-3-yloxy)-9H-pyrido[3,4-b]indole-1-carboxamide(38 mg, 0.081 mmol) and 4-nitrophenyl carbonochloridate (19.64 mg, 0.097mmol) in dichloromethane (2 mL) at room temperature was added pyridine(0.013 mL, 0.162 mmol). The resulting homogeneous mixture was stirred atroom temperature for 1 hr before 5-fluoroisoindoline hydrocloride (35.2mg, 0.203 mmol) and N,N-diisopropylethylamine (0.053 mL, 0.305 mmol) wasadded. The mixture was heated at 50° C. for 1 hr. It was concentratedunder vacuum, diluted with MeOH (1.8 mL), and was purified by reversephase HPLC. The correct fraction was concentrated under vacuum, basifiedwith saturated NaHCO₃ solution, and extracted with CH₂Cl₂ (3×30 mL). Thecombined extract was washed with brine (30 mL) and dried over anhydrousMgSO₄. Removal of solvent under vacuum provided the desired product(26.4 mg, 0.045 mmol, 54.9% yield) as a yellow solid. LCMS(M+H)⁺=566.34. ¹H NMR (500 MHz, DMSO-d₆) δ: 11.67 (s, 1H), 8.36 (m, 1H),8.18 (s, 1H), 8.12 (s, 1H), 7.79 (s, 1H), 7.64 (d, J=6.9 Hz, 1H),7.46-7.39 (m, 3H), 7.29 (dd, J1=9.0 Hz, J2=2.4 Hz, 1H), 7.23-7.17 (m,2H), 7.08 (d, J=8.6 Hz, 1H), 6.70 (dd, J1=8.7 Hz, J2=2.4 Hz, 1H), 5.10(m, 1H), 4.85 (s, 2H), 4.82 (s, 2H), 3.99 (dd, J1=10.5 Hz, J2=4.2 Hz,1H), 3.92-3.83 (m, 2H), 3.84 (m, 1H), 2.32 (m, 1H), 2.09 (m, 1H), 2.01(s, 3H).

EXAMPLE 197-(Cyanomethyl)-4-(3-(6-methoxy-1-oxoisoindolin-2-yl)-2-methylphenyl)-9H-pyrido[3,4-b]indole-1-carboxamide

1. Benzyl3-(1-(6-cyanomethyl)-1H-indol-3-yl)-2-nitroethyl)-2-methylphenylcarbamate

A mixture of (E)-benzyl-2-methyl-3-(2-nitrovinyl)phenylcarbamate (1.0 g,3.2 mmol) and 2-(1H-indol-6-yl)acetonitrile (0.55 g, 3.52 mmol) in water(50 mL) was heated at 105° C. for 24 hr. The reaction mixture was cooledto RT, diluted with water (50 mL) and extracted with EtOAc (2×200 mL).The combined extracts were washed with water, brine, dried over Na₂SO₄and concentrated. The residue was purified by silica gel columnchromatography, eluting with 35% EtOAc in hexane to give the desiredproduct (0.70 g, 1.49 mmol, 46.7%) as pale yellow sticky solid.

2. Benzyl3-(2-amino-6-(cyanomethyl)-1H-indol-3-yl)ethyl)-2-methylphenylcarbamate

To a solution of benzyl3-(1-(6-(cyanomethyl)-1H-indol-3-yl)-2-nitroethyl-2-methylphenylcarbamate(1.4 g, 2.99 mmol) in MeOH (60 mL) and THF (60 mL) was added zinc powder(2.93 g, 45 mmol) and ammonium chloride (2.4 g, 45 mmol) and the mixturewas stirred at RT for 5 h. Then the reaction mixture was diluted withEtOAc (25 mL), filtered over CELITE® and the filtrate was concentratedunder vacuum to give the desired product (1.30 g, 2.96 mmol, 99% yield)as pale brown sticky solid.

3. Ethyl4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-7-cyanomethyl)-9H-pyrido[3,4-b]indole-1-carboxylate

To a solution of benzyl3-(2-amino-1-(6-cyanomethyl)-1H-indol-3-yl)ethyl)-2-methylphenylcarbamate (1.30 g, 2.96 mmol) and ethyl glyoxylate (1.83 mL, 8.88mmol) in toluene (80 mL) and THF (30 mL) was added HCl in dioxane (4Msolution, 1.48 mL, 5.92 mmol). The reaction mixture was stirred at RTfor 48 hr. The solvents were removed under vacuum. The residue wasdiluted with water (50 mL), basified with 10% NaHCO₃ solution andextracted with EtOAc (2×200 mL). The combined extract was washed withwater, brine, dried over Na₂SO₄ and concentrated to give a crude cyclicintermediate. To the intermediate was added xylene (120 mL) and 10% Pd/C(1 g), and the mixture was heated at 125° C. for 10 h under inertatmosphere. Reaction mixture was cooled to room temperature, dilutedwith EtOAc and filtered over CELITE®. Filtrate was concentrated underreduced pressure to get crude product which was purified by silica gelcolumn chromatography. Elution of the column with 40% EtOAc in hexanegave the desired product (300 mg, 0.58 mmol, 19.6%) as yellow solid.

4. Benzyl3-(1-aminoxycarbonyl)-7-cyanomethyl)-9H-pyrido[3,4-b]indole-4-yl)-2-methylphenylcarbamate

Ethyl4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-7-cyanomethyl)-9H-pyrido[3,4-b]indole-1-carboxylate(300 mg, 0.58 mmol) was taken in mathanolic ammonia (25 mL, ≈15%solution) in pressure tube and heated at 100° C. for 2 h. Solvent wasevaporated under vacuum and the residue was purified by silica gelcolumn chromatography. Elution of the column with 30% EtOAc in hexanegave the desired product (170 mg, 0.35 mmol, 60%) as a yellow solid.

5.3-(1-Aminoxycarbonyl)-7-cyanomethyl)-9H-pyrido[3,4-b]indole-4-yl)-2-methylaniline

A mixture of benzyl3-(1-aminoxycarbonyl)-7-cyanomethyl)-9H-pyrido[3,4-b]indole-4-yl)-2-methylphenylcarbamate(170 mg, 0.35 mmol) and Pd/C (50 mg) in THF (10 mL) and MeOH (15 mL) wasstirred at room temperature under hydrogen atmosphere for 1.5 hr. Afterthat the reaction mixture was filtered over CELITE® pad and the filtratewas concentrated to give the desired product (120 mg, 0.33 mmol, 97%yield) as pale yellow sticky solid.

6.2-(3-(1-Carbamoyl-7-(cyanomethyl)-9H-pyrido-[3,4-b]indole-1-4-yl)-2-methylphenylamino)methyl)-5-methoxybenzoicacid

To a mixture of3-(1-aminoxycarbonyl)-7-cyanomethyl)-9H-pyrido[3,4-b]indole-4-yl-2-methylaniline(20 mg, 0.056 mmol), 2-formyl-5-methoxybenzoic aid (25.3 mg, 0.14 mmol)in 1,2 dichloroethane (1.6 mL) and THF (1 mL) were added sodiumtriacetoxyborohydride (35.6 mg, 0.168 mmol) and acetic acid (0.0085 mL,0.14 mmol) and stirred at room temperature for 24 h. Then the reactionmixture was diluted with water (10 mL) and extracted with EtOAc (2×20mL). Organic extracts were washed with water, brine, dried over Na₂SO₄and concentrated to give crude product, which was purified by silica gelcolumn chromatography. Elution of the column with 10% MeOH in chloroformgave desired product (25 mg, 50% pure product by LC-MS), which was usedin the next step without further purification.

7.7-(Cyanomethyl)-4-(3-(6-methoxy-1-oxoisoindolin-2-yl)-2-methylphenyl)-9H-pyrido[3,4-b]indole-1-carboxamide

To a solution of2-(3-(1-carbamoyl-7-(cyanomethyl)-9H-pyrido-[3,4-b]indole-1-4-yl)-2-methylphenylamino)methyl)-5-methoxybenzoicacid (25 mg, 0.048 mmol) in DMF (1.5 mL) were added BOP reagent (42.6mg, 0.096 mmol) and N-methylmorpholine (0.021 mL, 0.192 mmol) andstirred at 45° C. for 1 hr. Then the reaction mixture was cooled to roomtemperature, diluted with water (15 mL) and extracted with EtOAc (2×25mL). Combined organic extracts were washed with water, brine, dried overNa₂SO₄ and concentrated. The crude product obtained was purified bycolumn chromatography, eluting with 4% MeOH in CHCl₃ followed byrecrystallization with hexane/EtOAc to give7-(cyanomethyl)-4-(3-(6-methoxy-1-oxoisoindolin-2-yl)-2-methylphenyl)-9H-pyrido[3,4-b]indole-1-carboxamide(3.5 mg, 0.007 mmol, 15% yield) as a pale yellow solid. LCMS(M+H)=502.2. ¹H NMR (400 MHz, CDCl₃) δ: 10.44 (bs, 1H), 8.33 (s, 1H),8.00 (bs, 1H), 7.56 (s, 1H), 7.52-7.40 (m, 6H), 7.20-7.13 (m, 2H), 5.67(bs, 1H), 4.86-4.72 9 (m, 2H), 3.92 (s, 2H), 3.89 (s, 3H), 1.97 (s, 3H).

EXAMPLE 204-(3-(6-Chloro-1-oxoisoindolin-2-yl)-2-methylphenyl)-7-(cyanomethyl)-9H-pyrido[3,4-b]indole-1-carboxamide

1.2-(3-(1-Carbamoyl-7-(cyanomethyl)-9H-pyrido-[3,4-b]indole-1-4-yl)-2-methylphenylamino)methyl)-5-chlorobenzoicacid

A mixture of3-(1-aminoxycarbonyl)-7-cyanomethyl)-9H-pyrido[3,4-b]indole-4-yl-2-methylaniline7 (40 mg, 0.112 mmol), 5-chloro-2-formylbenzoic acid (51.6 mg, 0.28mmol) and 4 angstrom molecular sieves (0.5 g) in methanol (15 mL) wasstirred at RT for 24 h. After that the mixture was cooled to −20° C. andsodium borohydride (29.6 mg, 0.78 mmol) was added and the reactionmixture was allowed to warm up to 10° C. The solvent was removed underreduced pressure, quenched with saturated NH₄Cl solution (5 ml) andextracted with EtOAc (2×10 ml). Combined organic extracts were washedwith water, brine, dried over Na₂SO₄ and concentrated. The crude productobtained was purified by silica gel column chromatography eluting with5% MeOH in CHCl₃ to give the desired product (10 mg, 0.019 mmol, 17%yield) as a yellow sticky solid.

2.4-(3-(6-chloro-1-oxoisoindolin-2-yl)-2-methylphenyl)-7-(cyanomethyl)-9H-pyrido[3,4-b]indole-1-carboxamide

To a solution of2-(3-(1-carbamoyl-7-(cyanomethyl)-9H-pyrido-[3,4-b]indole-1-4-yl)-2-methylphenylamino)methyl)-5-chlorobenzoicacid (10 mg, 0.019 mmol) in DMF (0.6 mL) were added BOP reagent (16.9mg, 0.038 mmol) and N-methylmorpholine (0.0084 mL, 0.076 mmol) and themixture was stirred at 45° C. for 1 hr. Then the reaction mixture wascooled to RT, diluted with water (10 mL) and extracted with EtOAc (2×10mL). Combined organic extracts were washed with water, brine, dried overNa₂SO₄ and concentrated. The crude product obtained was purified bysilica gel column chromatography. Elution of the column with 3% MeOH inchloroform gave desired4-(3-(6-chloro-1-oxoisoindolin-2-yl)-2-methylphenyl)-7-(cyanomethyl)-9H-pyrido[3,4-b]indole-1-carboxamide(4.5 mg, 0.0089 mmol, 46% yield) as a pale yellow solid. ¹H NMR (400MHz, DMSO-d₆) δ: 11.93 (bs, 1H), 8.32 (s, 1H), 8.24 (s, 1H), 7.83-7.66(m, 5H), 7.55-7.51 (t, J=8.0 Hz, 1H), 7.44-7.42 (d, 1H), 7.28-7.26 (d,J=8.0 HZ, 1H), 7.03-7.01 (d, J=8.0 Hz, 1H), 5.07-4.90 (m, 2H), 4.19 (s,3H), 1.84 (s, 3H); LCMS (M−H)=504.0.

EXAMPLE 214-(3-(6-Chloro-1-oxoisoindolin-2-yl)-2-methylphenyl)-7-hydroxy-9H-pyrido[3,4-b]indole-1-carboxamide

To a heterogeneous mixture of4-(3-(6-chloro-1-oxoisoindolin-2-yl)-2-methylphenyl)-7-methoxy-9H-pyrido[3,4-b]indole-1-carboxamide(prepared in the same manner as Example 15) (0.277 g, 0.557 mmol) indichloromethane (20 mL) at 0° C. was added tribromoborane indichloromethane (2.79 mL, 2.79 mmol) over 5 min. The heterogeneousmixture was stirred at room temperature for 3 hr and then poured intoice cold water (20 mL). The resulting mixture was basified withsaturated NaHCO₃ solution to pH 8 and extracted with ethyl acetate (3×40mL). The combined extract was washed with brine (30 mL) and dried overanhydrous MgSO₄. Removal of solvent under vacuum provided the desiredproduct (0.217 g, 85% purity, 0.382 mmol, 68.5% yield) as a yellowsolid. A pure sample was obtained through prep. reverse phase HPLCpurification. LCMS (M+H)⁺=483.15. ¹H NMR (500 MHz, DMSO-d₆) δ: 11.61 (s,1H), 9.89 (s, 1H), 8.34 (s, 1H), 8.20 (s, 1H), 7.88 (s, 1H), 7.81-7.77(m, 3H), 7.72 (dd, J1=7.8 Hz, J2=1.2 Hz, 1H), 7.58 (m, 1H), 7.48 (dd,J1=7.5 Hz, J2=1.2 Hz, 1H), 7.23 (d, J=2.0 Hz, 1H), 7.12 (d, J=8.6 Hz,1H), 6.60 (dd, J1=8.7 Hz, J2=2.3 Hz, 1H), 5.10 (d, J=17.6 Hz, 1H), 4.99(d, J=17.6 Hz, 1H), 1.92 (s, 3H).

EXAMPLE 224-(3-(6-Chloro-1-oxoisoindolin-2-yl)-2-methylphenyl)-7-(3-hydroxypropoxy)-9H-pyrido[3,4-b]indole-1-carboxamide

A mixture of4-(3-(6-chloro-1-oxoisoindolin-2-yl)-2-methylphenyl)-7-hydroxy-9H-pyrido[3,4-b]indole-1-carboxamide(32 mg, 0.066 mmol) and cesium carbonate (25.9 mg, 0.080 mmol) in DMF (3mL) was heated at 75° C. for 4 hr. The mixture was diluted with ethylacetate (60 mL), washed with water (2×20 mL) and brine (20 mL), anddried over anhydrous MgSO₄. The organic solution was concentrated undervacuum and the residue was purified by reverse phase HPLC. The correctfraction was concentrated under vacuum, basified with saturated NaHCO₃solution, and extracted with ethyl acetate (3×30 mL). The combinedextract was washed with brine (30 mL) and dried over anhydrous MgSO₄.Removal of solvent under vacuum provided the desired product (6.2 mg,0.011 mmol, 16.6% yield) as a yellow solid. LCMS (M+H)⁺=541.28. ¹H NMR(500 MHz, DMSO-d₆) δ: 11.70 (s, 1H), 8.35 (s, 1H), 8.24 (s, 1H), 7.87(s, 1H), 7.80-7.78 (m, 3H), 7.72 (m, 1H), 7.59 (m, 1H), 7.50 (m, 1H),7.41 (d, J=2.2 Hz, 1H), 7.19 (d, J=8.9 Hz, 1H), 6.74 (dd, J1=8.9 Hz,J2=2.4 Hz, 1H), 5.09 (d, J=17.5 Hz, 1H), 5.00 (d, J=17.5 Hz, 1H), 4.17(m, 2H), 3.65 (m, 2H), 1.97 (m, 2H), 1.92 (s, 3H).

EXAMPLE 234-(3-(6-Chloro-1-oxoisoindolin-2-yl)-2-methylphenyl)-7-(2-morpholinoethoxy)-9H-pyrido[3,4-b]indole-1-carboxamide

A mixture of4-(3-(6-chloro-1-oxoisoindolin-2-yl)-2-methylphenyl)-7-hydroxy-9H-pyrido[3,4-b]indole-1-carboxamide(50 mg, 0.104 mmol), 4-(2-chloroethyl)morpholine, HCl (67.4 mg, 0.362mmol), and cesium carbonate (202 mg, 0.621 mmol) in DMF (6 mL) washeated at 100° C. for 3 hr. The mixture was diluted with ethyl acetate(100 mL) and filtered through CELITE®. The filtrate was washed withwater (2×30 mL) and brine (30 mL), and dried over anhydrous MgSO₄. Afterthe solvent was removed under vacuum, the residue was purified byreverse phase HPLC. The correct fractions were concentrated undervacuum, basified with saturated NaHCO₃ solution, and extracted withethyl acetate (3×30 mL). The combined extract was washed with brine (30mL) and dried over anhydrous MgSO₄. Removal of solvent under vacuumprovided the purified product (7.1 mg, 0.011 mmol, 10.9% yield) as apale yellow sold. LCMS (M+H)⁺=596.29. ¹H NMR (500 z, DMSO-d₆) δ: 11.72(s, 1H), 8.36 (s, 1H), 8.25 (s, 1H), 7.86 (s, 1H), 7.82-7.78 (m, 3H),7.72 (d, J=6.9 Hz, 1H), 7.59 (m, 1H), 7.50 (m, 1H), 7.43 (s, 1H), 7.22(br. S, 1H), 6.79 (br. S, 1H), 5.10 (d, J=17.6 Hz, 1H), 5.00 (d, J=17.6Hz, 1H), 4.23 (m, 2H), 3.81-3.53 (m, 8H), 2.81 (m, 2H), 1.92 (s, 3H).

EXAMPLE 244-(3-(6-Chloro-1-oxoisoindolin-2-yl)-2-methylphenyl)-7-(3-hydroxypyrrolidin-1-yl)-9H-pyrido[3,4-b]indole-1-carboxamide

1. 1-(1H-Indol-6-yl)pyrrolidin-3-ol

To a pressure tube containing a light orange, homogeneous solution of6-bromo-1H-indole (1.01 g, 5.15 mmol) in DMSO (8.58 mL) purged withnitrogen were added pyrrolidin-3-ol (4.49 g, 51.5 mmol), cesiumcarbonate (3.36 g, 10.30 mmol), copper(I) iodide (0.098 g, 0.515 mmol)and (S)-pyrrolidine-2-carboxylic acid (0.652 g, 5.67 mmol). The pressuretube was sealed and stirred at 95° C. for 5.5 hr. The reaction wascooled to room temperature and immersed in an ice-water bath. Ice water(20 mL) was added, and the mixture was stirred for 10 min. It wasextracted with EtOAc (4×75 mL), and the organic layers were combined,dried over MgSO₄, and concentrated in vacuo to give a residue which waspurified by flash chromatography using an ISCO 120 g column eluting with20-100% EtOAc/hexanes. Appropriate fractions were collected andconcentrated in vacuo to give the desired product (0.5215 g, 2.58 mmol,50.1% yield) as an off-white solid.

2. 6-(3-(tert-Butyldimethylsilyloxy)pyrrolidin-1-yl)-1H-indole

A homogeneous, colorless solution of 1-(1H-indol-6-yl)pyrrolidin-3-ol(0.1036 g, 0.512 mmol), tert-butylchlorodimethylsilane (0.093 g, 0.615mmol) and imidazole (0.087 g, 1.281 mmol) in DMF (2.56 mL) was stirredovernight. The mixture was diluted with EtOAc (75 mL), washed with water(4×25 mL) and brine (25 mL) successively, dried over MgSO₄, andconcentrated in vacuo. The residue was triturated with hexanes to givethe desired product (0.1600 g, 0.470 mmol, 92%).

3. Benzyl3-(1-(6-(3-(tert-butyldimethylsilyloxy)pyrrolidin-1-yl)-1H-indol-3-yl)-2-nitroethyl)-2-methylphenylcarbamate

6-(3-(tert-Butyldimethylsilyloxy)pyrrolidin-1-yl)-1H-indole (1.867 g,5.90 mmol) and (E)-benzyl 2-methyl-3-(2-nitrovinyl)phenylcarbamate(1.5354 g, 4.92 mmol) were dissolved in THF (40 mL), concentrated invacuo, and the mixture was heated at 110° C. for 1 hr. The reactionmixture was cooled to room temperature and purified by flashchromatography using an ISCO 220 g column eluting with 25-100%EtOAc/hexanes to give the desired product (1.0324 g, 1.642 mmol, 33.4%yield) as a tan solid.

4. Benzyl3-(2-amino-1-(6-(3-(tert-butyldimethylsilyloxy)pyrrolidin-1-yl)-1H-indol-3-yl)ethyl)-2-methylphenylcarbamate

To a solution of benzyl3-(1-(6-(3-(tert-butyldimethylsilyloxy)pyrrolidin-1-yl)-1H-indol-3-yl)-2-nitroethyl)-2-methylphenylcarbamate(1.0324 g, 1.642 mmol) and ammonium chloride (1.317 g, 24.63 mmol) inmethanol (32.8 mL) and tetrahydrofuran (32.8 mL) under nitrogen wasadded zinc (1.610 g, 24.63 mmol), and the reaction was stirredovernight. The solution was filtered through a pad of CELITE® and rinsedwith MeOH and THF. The filtrate was concentrated in vacuo, dissolved inEtOAc (100 mL) and water (40 mL). After separation of the layers, theaqueous layer was extracted with EtOAc (2×100 mL). The organic layerswere combined, dried over MgSO₄, filtered and concentrated in vacuo togive the desired product (1.007 g, 1.682 mmol, 102% yield) as a darksolid.

5. Ethyl4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-7-(3-(tert-butyldimethylsilyloxy)pyrrolidin-1-yl)-9H-pyrido[3,4-b]indole-1-carboxylate

To a solution of benzyl3-(2-amino-1-(6-(3-(tert-butyldimethylsilyloxy)pyrrolidin-1-yl)-1H-indol-3-yl)ethyl)-2-methylphenylcarbamate(0.1010 g, 0.169 mmol) in 1,4-dioxane (4.82 mL) was added 50% ethyl2-oxoacetate/toluene (0.067 mL, 0.337 mmol) at 10° C. The cold bath wasremoved, and the reaction was stirred to room temperature for 3 h. Thereaction was concentrated in vacuo to give crude ethyl4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-7-(3-(tert-butyldimethylsilyloxy)pyrrolidin-1-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-carboxylatewhich was used in the subsequent step. This was added to p-xylene (41.6mL) and 10% Pd/C (0.310 g, 0.291 mmol). The reaction was heated to 125°C. for 4.5 hr and cooled to room temperature. The solution was filteredthrough a pad of CELITE® and rinsed with EtOAc (150 mL). The filtratewas washed with water (40 mL), dried over MgSO₄, filtered andconcentrated in vacuo to give a residue which was purified by flashchromatography using an ISCO 120 g column eluting with 0-30%EtOAc/CH₂Cl₂. Appropriate fractions (20% elution) were combined,concentrated in vacuo to give the desired product (0.1487 g, 0.219 mmol,15.0% yield) as a tan solid.

6. Ethyl4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-7-(3-(tert-butyldimethylsilyloxy)pyrrolidin-1-yl)-9H-pyrido[3,4-b]indole-1-carboxylate

To a burgundy, homogeneous solution of ethyl4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-7-(3-(tert-butyldimethylsilyloxy)pyrrolidin-1-yl)-9H-pyrido[3,4-b]indole-1-carboxylate(0.1487 g, 0.219 mmol) in tetrahydrofuran (7.47 mL) and methanol (2.489mL) was added a solution of LiOH hydrate (0.037 g, 0.876 mmol) in water(2 mL). After 2.5 h, the reaction was concentrated in vacuo not todryness, and the solution was dissolved in water (8 mL). 1 N aqueous HClwas added until pH 5-6 by litmus paper. The precipitate was filtered anddried over Drierite to give the desired product (0.1323 g, 0.203 mmol,93% yield) as a brown solid.

7. Benzyl3-(7-(3-(tert-butyldimethylsilyloxy)pyrrolidin-1-yl)-1-carbamoyl-9H-pyrido[3,4-b]indol-4-yl)-2-methylphenylcarbamate

A burgundy, homogeneous solution of4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-7-(3-(tert-butyldimethylsilyloxy)pyrrolidin-1-yl)-9H-pyrido[3,4-b]indole-1-carboxylicacid (0.1323 g, 0.203 mmol), ammonium chloride (0.043 g, 0.813 mmol),BOP (0.117 g, 0.264 mmol), DIPEA (0.170 mL, 0.976 mmol) andN-methylmorpholine (0.087 mL, 0.793 mmol) in DMF (1.694 mL) was stirredfor 1 h. Water (20 mL) was added, and the precipitate was filtered anddried over Drierite to give benzyl the desired product (0.1164 g, 0.179mmol, 88% yield) as a brown solid.

8.4-(3-Amino-2-methylphenyl)-7-(3-(tert-butyldimethylsilyloxy)pyrrolidin-1-yl)-9H-pyrido[3,4-b]indole-1-carboxamide

A solution of benzyl3-(7-(3-(tert-butyldimethylsilyloxy)pyrrolidin-1-yl)-1-carbamoyl-9H-pyrido[3,4-b]indol-4-yl)-2-methylphenylcarbamate(0.1164 g, 0.179 mmol) and 10% Pd/C (0.019 g, 0.018 mmol) in methanol(6.7 mL) and tetrahydrofuran (2.2 mL) under hydrogen was stirred for 45min. After purging with nitrogen, the reaction was filtered through apad of CELITE® and rinsed with MeOH. The filtrate was concentrated invacuo, dissolved in CH₂Cl₂ (75 mL) and washed with brine (25 mL). Theorganic layer was dried over MgSO₄ and concentrated in vacuo to give thedesired product (0.0782 g, 0.152 mmol, 85% yield) as a brick-red solid.

9.2-((3-(7-(3-(tert-Butyldimethylsilyloxy)pyrrolidin-1-yl)-1-carbamoyl-9H-pyrido[3,4-b]indol-4-yl)-2-methylphenylamino)methyl)-5-chlorobenzoicacid

To a homogeneous, light orange solution of4-(3-amino-2-methylphenyl)-7-(3-(tert-butyldimethylsilyloxy)pyrrolidin-1-yl)-9H-pyrido[3,4-b]indole-1-carboxamide(0.0782 g, 0.152 mmol), 5-chloro-2-formylbenzoic acid (0.070 g, 0.379mmol), and acetic acid (0.022 mL, 0.379 mmol) in dichloromethane (3.03mL) and tetrahydrofuran (2.022 mL) under nitrogen was added sodiumtriacetoxyborohydride (0.096 g, 0.455 mmol), and the mixture was stirredovernight. Water (3 mL) was added, and the reaction was stirred at rtfor 10 min. EtOAc (50 mL) and water (20 mL) were added, and the layerswere separated. The organic layer was washed with water (6×20 mL) andbrine (20 mL), dried over MgSO₄, and concentrated in vacuo to give acrude product which was used in the subsequent step.

10.7-(3-(tert-Butyldimethylsilyloxy)pyrrolidin-1-yl)-4-(3-(6-chloro-1-oxoisoindolin-2-yl)-2-methylphenyl)-9H-pyrido[3,4-b]indole-1-carboxamide

A solution of2-((3-(7-(3-(tert-butyldimethylsilyloxy)pyrrolidin-1-yl)-1-carbamoyl-9H-pyrido[3,4-b]indol-4-yl)-2-methylphenylamino)methyl)-5-chlorobenzoicacid (0.104 g, 0.152 mmol), DIPEA (0.080 mL, 0.456 mmol),N-methylmorpholine (0.134 mL, 1.216 mmol) and BOP (0.175 g, 0.395 mmol)in DMF (1.520 mL) under nitrogen was heated at 45° C. for 1 h. Thereaction was cooled to room temperature, dissolved in EtOAc (100 mL) andwashed with water (3×25 mL) and brine (25 mL), dried over MgSO₄,filtered and concentrated in vacuo to give a residue which was purifiedby flash chromatography using an ISCO 12 g column eluting with 0-20EtOAc/hexanes. Appropriate fractions were collected and concentrated invacuo to give the desired product (0.0456 g, 0.068 mmol, 45.0% yield) asa light orange solid.

11.4-(3-(6-Chloro-1-oxoisoindolin-2-yl)-2-methylphenyl)-7-(3-hydroxypyrrolidin-1-yl)-9H-pyrido[3,4-b]indole-1-carboxamide

To a homogeneous, orange solution of7-(3-(tert-butyldimethylsilyloxy)pyrrolidin-1-yl)-4-(3-(6-chloro-1-oxoisoindolin-2-yl)-2-methylphenyl)-9H-pyrido[3,4-b]indole-1-carboxamide(0.0456 g, 0.068 mmol) in tetrahydrofuran (0.684 mL) under nitrogen wasadded 1 M TBAF/THF (0.103 mL, 0.103 mmol). The reaction was stirred for75 min and concentrated in vacuo. The residue was dissolved in DMSO (0.2mL) and MeOH, and subjected to autoprep HPLC. The appropriate fractionswere collected, basified with NaHCO₃ (solid), and concentrated in vacuo.The residue was extracted with CH₂Cl₂ (3×). The combined extract wasdried over Na₂SO₄ and concentrated in vacuo to give the desired product(0.0112 g, 0.020 mmol, 29.7% yield) as a light yellow solid. LC/MS(M+H)=552.11; ¹H NMR (500 MHz, DMSO-d₆) (recognizable peaks for majoratropoisomer) δ ppm 11.26 (s, 1H), 8.21 (d, J=2.8 Hz, 1H), 8.08 (s, 1H),7.81 (s, 1H), 7.74 (d, J=1.94 Hz, 2H), 7.63-0.65 (m, 2H), 7.45-7.58 (m,1H), 7.42 (d, J=1.11 Hz, 1H), 7.03 (d, J=8.60 Hz, 1H), 6.83 (d, J=1.66Hz, 1H), 6.38 (dd, J1=9.0 Hz, J2=2.1 Hz, 1H), 5.02 (d, J=17.76 Hz, 1H),4.95-4.98 (m, 1H), 4.94 (d, J=17.76 Hz, 1H), 4.43 (br. S, 1H), 3.47(ddd, J1=10.2 Hz, J2=4.8 Hz, J3=2.2 Hz, 1H), 3.37-3.44 (m, 1H),3.31-3.37 (m, 1H), 3.15 (d, J=10.0 Hz, 1H), 2.07 (dd, J=8.25, 4.30 Hz,1H), 1.90-1.96 (m, 1H), 1.88 (s, 3H).

EXAMPLE 254-(3-(6-Chloro-1-oxoisoindolin-2-yl)-2-methylphenyl)-7-(tetrahydrofuran-3-ylamino)-9H-pyrido[3,4-b]indole-1-carboxamide

1. 2-(Trimethylsilyl)ethyl 1H-indol-6-ylcarbamate

To a yellow, homogeneous solution of 1H-indol-6-amine (1.3007 g, 9.84mmol) and DIPEA (2.58 mL, 14.76 mmol) in 1,4-dioxane (19.68 mL) undernitrogen was added 2,5-dioxopyrrolidin-1-yl 2-(trimethylsilyl)ethylcarbonate (2.81 g, 10.83 mmol) The reaction was stirred overnight,diluted with EtOAc (1500 mL), washed with water (3×50 mL) and brine (50mL), dried over MgSO₄, filtered and concentrated in vacuo to give thedesired product (2.666 g, 9.65 mmol, 98% yield) as a light tan solid.

2. 2-(Trimethylsilyl)ethyl3-(1-(2-methyl-3-(benzyloxycarbonylamino)-2-nitroethyl)-1H-indol-6-ylcarbamate

2-(Trimethylsilyl)ethyl 1H-indol-6-ylcarbamate (2.666 g, 9.65 mmol) and(E)-benzyl 2-methyl-3-(2-nitrovinyl)phenylcarbamate (3.62 g, 11.58 mmol)were dissolved in THF (50 mL), concentrated in vacuo, and the mixturewas melted at 115° C. for 6.5 h. The reaction was cooled to roomtemperature and purified by flash chromatography using an ISCO 330 gcolumn eluting with 30-75% EtOAc/hexanes to give the desired product(2.184 g, 3.71 mmol, 38.5% yield) as a light brown solid.

3. 2-(Trimethylsilyl)ethyl3-(1-(2-methyl-3-(benzyloxycarbonylamino)-2-aminoethyl)-1H-indol-6-ylcarbamate

To a light brown, homogeneous solution of 2-(trimethylsilyl)ethyl3-(1-(2-methyl-3-(benzyloxycarbonylamino)-2-nitroethyl)-1H-indol-6-ylcarbamate(2.1655 g, 3.68 mmol) in tetrahydrofuran (73.6 mL) and methanol (73.6mL) under nitrogen were added ammonium chloride (2.95 g, 55.2 mmol) andzinc (3.61 g, 55.2 mmol). After 5.25 h, the solution was filteredthrough a pad of CELITE®, rinsed with MeOH, and the filtrate wasconcentrated in vacuo. The residue was dissolved in CH₂Cl₂ (100 mL) andwashed with water (2×30 mL) and brine (30 mL) successively. The organicsolution was dried over MgSO₄ and concentrated in vacuo to give thedesired product (2.1981 g, 3.93 mmol, 107% yield) as a light violetfoam.

4. Ethyl4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-7-((2-(trimethylsilyl)ethoxy)carbonylamino)-9H-pyrido[3,4-b]indole-1-carboxylate

To a light orange, homogeneous solution of 2-(trimethylsilyl)ethyl3-(1-(2-methyl-3-(benzyloxycarbonylamino)-2-aminoethyl)-1H-indol-6-ylcarbamate(1.111 g, 1.988 mmol) in 1,4-dioxane (56.8 mL) and 50% ethyl2-oxoacetate/toluene (0.985 mL, 4.97 mmol) under nitrogen was added 4Nhydrochloric acid/dioxane (1.243 mL, 4.97 mmol). The reaction wasstirred overnight. More 50% ethyl 2-oxoacetate/toluene (0.985 mL, 4.97mmol) and 4 N HCl/dioxane (0.5 mL) were added. The reaction was stirredovernight. This was combined with another similar reaction mixture(1.919 mmol scale), concentrated in vacuo, dissolved in EtOAc (75 mL)and washed with water (30 mL) and brine (30 mL), successively. Theorganic solution was dried over MgSO₄, filtered and concentrated invacuo to give a crude product as a burgundy foam which was used in thesubsequent step. This was added to p-xylene (112 mL) and 10% Pd/C (0.832g, 0.781 mmol). The reaction was heated to 115° C. After 6.5 hr, thesolution was cooled to room temperature and filtered through a pad ofCELITE® and rinsed with EtOAc (150 mL). The filtrate was washed withwater (40 mL), dried over MgSO₄, and concentrated in vacuo. Xylene wasremoved via short-path distillation to give a residue which was purifiedby flash chromatography using an ISCO 220 g column eluting with 40-100%EtOAc/hexane. Appropriate fractions (45-55% elution) were combined,concentrated in vacuo to give the desired product (0.5133 g, 0.804 mmol,20.57% yield) as a tan solid.

5.4-(3-(Benzyloxycarbonylamino)-2-methylphenyl)-7-((2-(trimethylsilyl)ethoxy)carbonylamino)-9H-pyrido[3,4-b]indole-1-carboxylicacid

To a homogeneous, burgundy solution of ethyl4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-7-((2-(trimethylsilyl)ethoxy)carbonylamino)-9H-pyrido[3,4-b]indole-1-carboxylate(0.565 g, 0.884 mmol) in tetrahydrofuran (30.2 mL) and methanol (10.05mL) was added a solution of lithium hydroxide hydrate (0.148 g, 3.54mmol) in water (4 mL). After 1 hr, the reaction was concentrated invacuo, acidified with 1 N aqueous HCl to pH ˜5 by litmus paper. Theprecipitate was filtered, dried over Drierite to give the desiredproduct (0.419 g, 0.686 mmol, 78% yield) as a light brown solid.

6.4-(3-(Benzyloxycarbonylamino)-2-methylphenyl)-7-((2-(trimethylsilyl)ethoxy)carbonylamino)-9H-pyrido[3,4-b]indole-1-carboxamide

To a dark, homogeneous solution of4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-7-((2-(trimethylsilyl)ethoxy)carbonylamino)-9H-pyrido[3,4-b]indole-1-carboxylicacid (0.4181 g, 0.685 mmol) in DMF (2.74 mL) were added ammoniumchloride (0.146 g, 2.74 mmol), BOP (0.394 g, 0.890 mmol), DIPEA (0.574mL, 3.29 mmol) and N-methylmorpholine (0.294 mL, 2.67 mmol). After 2.5hr, water was added, and the precipitate was collected and dried overDrierite to give the desired product (0.365 g, 0.599 mmol, 87% yield) asa light brown solid.

7. 2-(Trimethylsilyl)ethyl4-(3-amino-2-methylphenyl)-1-carbamoyl-9H-pyrido[3,4-b]indol-7-ylcarbamate

A solution of4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-7-((2-(trimethylsilyl)ethoxy)carbonylamino)-9H-pyrido[3,4-b]indole-1-carboxylicacid (0.2535 g, 0.533 mmol, 89% yield) and 10% Pd/C (0.064 g, 0.060mmol) in methanol (22.39 mL) and tetrahydrofuran (7.46 mL) washydrogenated for 1 hr. The reaction mixture was filtered through a padof CELITE® and rinsed with MeOH. The filtrate was concentrated in vacuo,dissolved in CH₂Cl₂ (75 mL) and washed with brine (25 mL). The organiclayer was dried over MgSO₄ and concentrated in vacuo to give the desiredproduct (0.254 g, 0.533 mmol, 89% yield) as a light brown solid.

8.2-((3-(1-Carbamoyl-7-((2-(trimethylsilyl)ethoxy)carbonylamino)-9H-pyrido[3,4-b]indol-4-yl)-2-methylphenylamino)methyl)-5-chlorobenzoicacid

To a homogeneous, light burgundy solution of 2-(trimethylsilyl)ethyl4-(3-amino-2-methylphenyl)-1-carbamoyl-9H-pyrido[3,4-b]indol-7-ylcarbamate(0.2535 g, 0.533 mmol), 5-chloro-2-formylbenzoic acid (0.246 g, 1.332mmol), and acetic acid (0.076 mL, 1.332 mmol) in dichloromethane (10.66mL) and tetrahydrofuran (7.11 mL) under nitrogen was added sodiumtriacetoxyborohydride (0.339 g, 1.599 mmol). The reaction was stirredovernight. Water (5 mL) was added, and the reaction was stirred for 10min. EtOAc (50 mL) and water (20 mL) were added, and the layers wereseparated. The organic layer was washed with water (6×20 mL) and brine(20 mL), dried over MgSO₄, and concentrated in vacuo to give a crudeproduct that was used in the subsequent step.

9. 2-(Trimethylsilyl)ethyl1-carbamoyl-4-(3-(6-chloro-1-oxoisoindolin-2-yl)-2-methylphenyl)-9H-pyrido[3,4-b]indol-7-ylcarbamate

A solution of2-((3-(1-carbamoyl-7-((2-(trimethylsilyl)ethoxy)carbonylamino)-9H-pyrido[3,4-b]indol-4-yl)-2-methylphenylamino)methyl)-5-chlorobenzoicacid (0.343 g, 0.533 mmol), DIPEA (0.279 mL, 1.599 mmol),N-methylmorpholine (0.469 mL, 4.26 mmol) and BOP (0.613 g, 1.386 mmol)in DMF (5.33 mL) under nitrogen was heated at 45° C. for 45 min. Thereaction was cooled to room temperature, dissolved in EtOAc (100 mL) andwashed with water (3×25 mL) and brine (25 mL), dried over MgSO₄, andconcentrated in vacuo to give a residue which was purified by flashchromatography using an ISCO 40 g column eluting with 30-75%EtOAc/hexanes. Appropriate fractions were collected and concentrated invacuo to give the desired product (0.140 g, 0.224 mmol, 41.9% yield) asa light orange solid.

10.7-Amino-4-(3-(6-chloro-1-oxoisoindolin-2-yl)-2-methylphenyl)-9H-pyrido[3,4-b]indole-1-carboxamide

To a burgundy, homogeneous solution of 2-(trimethylsilyl)ethyl1-carbamoyl-4-(3-(6-chloro-1-oxoisoindolin-2-yl)-2-methylphenyl)-9H-pyrido[3,4-b]indol-7-ylcarbamate(0.126 g, 0.201 mmol) in tetrahydrofuran (0.2 mL) was added 1M TBAF/THF(0.402 mL, 0.402 mmol). After 4 hr, EtOAc (80 mL) was added, and thelayer was washed with water (20 mL) and brine (20 mL), successively. Theorganic solution was dried over MgSO₄ and concentrated in vacuo to givea crude product as a light brown solid, which was used in the subsequentstep.

11.4-(3-(6-Chloro-1-oxoisoindolin-2-yl)-2-methylphenyl)-7-(tetrahydrofuran-3-ylamino)-9H-pyrido[3,4-b]indole-1-carboxamide

To a light burgundy, homogeneous solution of7-amino-4-(3-(6-chloro-1-oxoisoindolin-2-yl)-2-methylphenyl)-9H-pyrido[3,4-b]indole-1-carboxamide(0.0695 g, 0.144 mmol), dihydrofuran-3(2H)-one (0.050 g, 0.577 mmol) andacetic acid (0.041 mL, 0.721 mmol) in dichloromethane (1.602 mL) and THF(1.602 mL) was added sodium triacetoxyborohydride (0.122 g, 0.577 mmol).The reaction was stirred overnight. Water (2 mL) was added, and thesolution was stirred at room temperature for 10 min. EtOAc (50 mL) andwater (20 mL) were added. After separation of layers, the organic layerwas washed with sat. aq. NaHCO₃, brine (20 mL), dried over MgSO₄, andconcentrated in vacuo to give a residue which was diluted with DMSO (0.2mL) and MeOH (0.8 mL) and purified by reverse phase HPLC. Theappropriate fractions were collected, basified with NaHCO₃ (solid), andconcentrated in vacuo. The residue was extracted with CH₂Cl₂ (3×). Thecombined extract was dried over Na₂SO₄ and concentrated in vacuo to givethe desired product (0.00234 g, 4.03 μmol, 2.79% yield) as a tan solid.LC/MS (M+H)=552.24.

EXAMPLE 264-(2-Fluoro-3-(6-methyl-1-oxoisoindolin-2-yl)phenyl)-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indole-1-carboxamide

1. Benzyl 3-cyano-2-fluorophenylcarbamate

To a light brown solution of 3-amino-2-fluorobenzonitrile (2.7141 g,19.94 mmol) and potassium carbonate (4.13 g, 29.9 mmol) in THF (166 mL)was syringed benzyl carbonochloridate (4.49 mL, 29.9 mmol) undernitrogen, and the reaction was stirred overnight. The insoluble materialwas filtered, and the filtrate was concentrated in vacuo. The residuewas dissolved in EtOAc (200 mL) and washed with 1 N aqueous HCl (50 mL),water (50 mL) and brine (50 mL), successively. The organic solution wasdried over MgSO₄ and concentrated in vacuo to give crude product whichwas stirred in hexanes (75 mL) for 1 hr. The insoluble material wasfiltered and washed with hexanes to give the desired product (4.4541 g,16.48 mmol, 83% yield) as a light tan solid.

2. Benzyl 2-fluoro-3-formylphenylcarbamate

To a slightly tan, homogeneous solution of benzyl3-cyano-2-fluorophenylcarbamate (4.45 g, 16.47 mmol) in THF (211 mL) ina −78° C. bath under nitrogen was syringed DIBAL-H (65.9 mL, 65.9mmol)/CH₂Cl₂ dropwise over 75 min. The reaction was stirred for 30 min.The cold bath was removed, and the reaction was stirred to roomtemperature. After 4 hr, the solution was added to ice-cold water (300mL) over 50 minutes; heavy emulsion ensued. After stirring for another30 min, the organic layer was separated, and the aqueous layer/emulsionwas filtered, and the insoluble materials were rinsed with CH₂Cl₂ (200mL). The organic layers were combined and concentrated in vacuo. Theresidue was dissolved in CH₂Cl₂ (300 mL) and washed with brine (75 mL),dried over MgSO₄, and concentrated in vacuo to give the desired product(4.0253 g, 11.78 mmol, 71.6% yield) as a tan solid.

3. (E)-Benzyl 2-fluoro-3-(2-nitrovinyl)phenylcarbamate

A solution of benzyl 2-fluoro-3-formylphenylcarbamate (4.0253 g, 14.73mmol), nitromethane (1.98 mL, 36.8 mmol) and nitromethane (1.979 mL,36.8 mmol) in acetic acid (49.1 mL) under nitrogen was heated at 90° C.After 2 hr, the reaction was cooled to room temperature and concentratedin vacuo. The residue was dissolved in CH₂Cl₂ (75 mL) and water (75 mL),and Na₂CO₃ (s) was added until pH basic by litmus paper. Afterseparation of layers, the aqueous layer was extracted with CH₂Cl₂ (3×75mL). The organic layers were combined and washed with brine (50 mL),dried over MgSO₄, and concentrated in vacuo to give the desired product(4.251 g, 10.08 mmol, 68.4% yield) as a burgundy oil.

4. Methyl 2,5-dimethylbenzoate

A colorless, homogeneous solution of 2,5-dimethylbenzoic acid (6.3264 g,42.1 mmol) and 4 N HCl/1,4-dioxane (11.58 mL, 46.3 mmol) was refluxedunder nitrogen. After 2.5 hr, the reaction was cooled to roomtemperature and concentrated in vacuo. The residue was dissolved inEtOAc (100 mL) and washed with water (40 mL), 1N aq. NaOH (40 mL), water(40 mL) and brine (40 mL), successively. The organic solution was driedover MgSO₄ and concentrated in vacuo to give the desired product (5.934g, 34.7 mmol, 82% yield) as a colorless oil.

5. Methyl 2-(bromomethyl)-5-methylbenzoate

A light yellow, homogeneous solution of methyl 2,5-dimethylbenzoate(4.467 g, 27.2 mmol), 1-bromopyrrolidine-2,5-dione (4.84 g, 27.2 mmol)and benzoic peroxyanhydride (0.659 g, 2.72 mmol) in benzene (136 mL)under nitrogen was refluxed. After 8.5 hr, the reaction was cooled toroom temperature. The succinimide was filtered, rinsed with benzene andthe filtrate was concentrated in vacuo. The residue was dissolved inEtOAc (100 mL) and washed with water (50 mL) and brine (50 mL), driedover MgSO₄, and concentrated in vacuo to give crude product that was amixture of the desired product and its regioisomer. This crude productwas used in the next step without further purification.

6. 6-Methylisobenzofuran-1(3H)-one

A heterogeneous, colorless solution of methyl2-(bromomethyl)-5-methylbenzoate and regioisomer (27.2 mmol) and calciumcarbonate (16.33 g, 163 mmol) in 1,4-dioxane (194 mL) and water (194 mL)was refluxed. After 5 hr, the reaction was cooled to room temperature.The insolubles were filtered, and the filtrate was concentrated invacuo. The residue was extracted with CH₂Cl₂ (2×200 mL). The organiclayers were combined, dried over MgSO₄, and concentrated in vacuo togive an oil which was purified by flash chromatography using an ISCO 220g column eluting with 10-50% EtOAc/hexanes. Appropriate fractions werecollected and concentrated in vacuo to give the desired product (1.205g, 8.13 mmol, 29.9% yield) as a white solid.

7. 2-(Hydroxymethyl)-5-methylbenzoic acid

A colorless, homogeneous solution of 6-methylisobenzofuran-1(3H)-one(0.95 g, 6.41 mmol), KOH (0.576 g, 10.26 mmol) in methanol (20.52 mL)and water (5.13 mL) was refluxed. After two hr, the reaction was cooledto room temperature, concentrated in vacuo, and acidified with 1 Maqueous KHSO₄ to pH ˜3. The mixture was extracted with EtOAc (4×50 mL).The combined extract was dried over MgSO₄ and concentrated in vacuo togive the desired product (0.632 g, 3.81 mmol, 59.4% yield) as a whitesolid.

8. 2-Formyl-5-methylbenzoic acid

To a homogeneous, colorless solution of2-(hydroxymethyl)-5-methylbenzoic acid (0.6325 g, 3.81 mmol) in THF (35mL) under nitrogen was added MnO₂ (4.96 g, 57.1 mmol), and the reactionwas stirred overnight. Additional MnO₂ (˜3 g) was added, and thereaction was stirred overnight. The mixture was filtered through a padof CELITE® and rinsed with THF. The filtrate was concentrated in vacuoto give the desired product (0.3302 g, 2.011 mmol, 52.8% yield) as anoff-white solid.

9. Benzyl2-fluoro-3-(1-(6-(2-methoxyethoxy)-1H-indol-3-yl)-2-nitroethyl)phenylcarbamate

6-(2-Methoxyethoxy)-1H-indole (1.198 g, 6.26 mmol) and (E)-benzyl2-fluoro-3-(2-nitrovinyl)phenylcarbamate (1.651 g, 5.22 mmol) weredissolved in THF (50 mL) and concentrated in vacuo, and the mixture washeated at 125° C. overnight. The reaction was cooled to roomtemperature, and the crude product was purified by flash chromatography(solid loading) using an ISCO 220 g column eluting with 15-75%EtOAc/hexanes to give the desired product (1.888 g, 3.61 mmol, 69.2%yield) as a light orange foam.

10. Benzyl3-(2-amino-1-(6-(2-methoxyethoxy)-1H-indol-3-yl)ethyl)-2-fluorophenylcarbamate

To a solution of benzyl2-fluoro-3-(1-(6-(2-methoxyethoxy)-1H-indol-3-yl)-2-nitroethyl)phenylcarbamate(3.75 g, 7.39 mmol) and ammonium chloride (5.93 g, 111 mmol) in methanol(148 mL) and tetrahydrofuran (148 mL) under nitrogen was added zinc(7.25 g, 111 mmol). After 3 hr, the reaction was filtered through a padof CELITE®, rinsed with EtOAc and MeOH. The filtrate was concentrated invacuo. Water (40 mL) was added followed by saturated aq. NaHCO₃ (to pH˜11 by litmus paper) and extracted with EtOAc (4×50 mL). The organiclayers were combined, washed with brine (40 mL), dried over MgSO₄, andconcentrated in vacuo to give the desired product (3.523 g, 6.35 mmol,86% yield) as a light tan solid.

11. Ethyl4-(3-(benzyloxycarbonylamino)-2-fluorophenyl)-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indole-1-carboxylate

To a light homogeneous, orange solution of benzyl3-(2-amino-1-(6-(2-methoxyethoxy)-1H-indol-3-yl)ethyl)-2-fluorophenylcarbamate(3.5215 g, 7.37 mmol) and ethyl 2-oxoacetate (2.92 mL, 14.75 mmol) (50%in toluene) under nitrogen was added 4N HCl/1,4-dioxane (2.212 mL, 8.85mmol); reaction turned dark burgundy. The reaction was stirredovernight, concentrated in vacuo, dissolved in EtOAc (50 mL) andsaturated aqueous NaHCO₃ (20 mL). After separation of the layers, theaqueous layer was extracted with EtOAc (3×50 mL). The organic layerswere combined, washed with brine (30 mL), dried over MgSO₄, andconcentrated in vacuo to give crude product which was used in subsequentstep. This was added to 10% Pd/C (1.569 g, 1.474 mmol) in p-xylene (211mL), and the solution was heated at 125° C. After 3.5 hr, the reactionwas cooled to room temperature, filtered through a pad of CELITE®, andthe insolubles were rinsed with EtOAc (250 mL). The filtrate was washedwith brine (75 mL), and the layers were separated. The organic layer wasdried over MgSO₄, filtered and concentrated in vacuo to give a residuewhich was purified by flash chromatography using an ISCO 220 g columneluting with 5-40% EtOAc/CH₂Cl₂. Appropriate fractions (20-25% elution)were collected and concentrated in vacuo to give the desired product(0.811 g, 1.381 mmol, 18.7% yield) as a light orange solid.

12.4-(3-(Benzyloxycarbonylamino)-2-fluorophenyl)-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indole-1-carboxylicacid

To a light orange, homogeneous solution of ethyl4-(3-(benzyloxycarbonylamino)-2-fluorophenyl)-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indole-1-carboxylate(0.8002 g, 1.435 mmol) in THF (30.8 mL) and MeOH (10.25 mL) was added asolution of LiOH hydrate (0.241 g, 5.74 mmol) in water (2 mL). After 1.5hr. the reaction was concentrated in vacuo. Water (10 mL) was addedfollowed by 1 N aqueous HCl to pH 4-5 by litmus paper. The precipitatewas filtered and washed with water, dried over Drierite under vacuum togive the desired product (0.705 g, 1.331 mmol, 93% yield) as a tansolid.

13. Benzyl3-(1-carbamoyl-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indol-4-yl)-2-fluorophenylcarbamate

A burgundy, homogeneous solution of4-(3-(benzyloxycarbonylamino)-2-fluorophenyl)-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indole-1-carboxylicacid (0.7 g, 1.322 mmol), ammonium chloride (0.283 g, 5.29 mmol), BOP(0.760 g, 1.719 mmol), DIPEA (1.108 mL, 6.35 mmol) andN-methylmorpholine (0.567 mL, 5.16 mmol) in DMF (8 mL) under nitrogenwas stirred. After 2 hr, water (20 mL) was added, and the reaction wasstirred at room temperature for 45 min. The precipitate was collected,rinsed with water and dried over Drierite under vacuum to give thedesired product (0.6318 g, 1.195 mmol, 90% yield) as a tan solid.

14.4-(3-Amino-2-fluorophenyl)-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indole-1-carboxamide

A solution of benzyl3-(1-carbamoyl-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indol-4-yl)-2-fluorophenylcarbamate(0.6318 g, 1.195 mmol) and 10% Pd/C (0.191 g, 0.179 mmol) in THF (31.9mL) and MeOH (47.8 mL) was hydrogenated. After 2 hr, the reaction wasfiltered through a wad of CELITE® and rinsed with THF and MeOH. Thefiltrate was concentrated in vacuo, dissolved in EtOAc (100 mL) andbrine (25 mL). The layers were separated, and the aqueous layer wasextracted with EtOAc (50 mL). The organic layers were combined, driedover MgSO₄, and concentrated in vacuo to give the desired product(0.4462 g, 1.007 mmol, 84% yield) as a tan solid.

15.2-((3-(1-Carbamoyl-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indol-4-yl)-2-fluorophenylamino)methyl)-5-methylbenzoicacid

To a light orange, homogeneous solution of4-(3-amino-2-fluorophenyl)-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indole-1-carboxamide(0.0767 g, 0.194 mmol), 2-formyl-5-methylbenzoic acid (0.096 g, 0.583mmol) and acetic acid (0.033 mL, 0.583 mmol) in dichloromethane (3.89mL) and THF (2.59 mL) under nitrogen was added sodiumtriacetoxyborohydride (0.206 g, 0.972 mmol). The reaction was stirredovernight. More sodium triacetoxyborohydride (0.206 g, 0.972 mmol) andacetic acid (0.033 mL, 0.583 mmol) were added. After 4.5 hr, water (3mL) was added, and the reaction was stirred for 10 min. EtOAc (50 mL)and water (20 mL) were added, and the layers were separated. The organiclayer was washed with water (6×20 mL) and brine (20 mL), dried overMgSO₄, and concentrated in vacuo to give a crude product used insubsequent step.

16.4-(2-Fluoro-3-(6-methyl-1-oxoisoindolin-2-yl)phenyl)-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indole-1-carboxamide

A homogeneous, orange solution of2-((3-(1-carbamoyl-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indol-4-yl)-2-fluorophenylamino)methyl)-5-methylbenzoicacid (0.105 g, 0.194 mmol), BOP (0.257 g, 0.582 mmol), DIPEA (0.119 mL,0.679 mmol) and N-methylmorpholine (0.192 mL, 1.746 mmol) in DMF (1.940mL) under nitrogen was heated at 45° C. After 45 min, the reaction wascooled to room temperature, dissolved in EtOAc (75 mL) and washed withwater (4×30 mL) and brine (30 mL), successively. The organic solutionwas dried over MgSO₄ and concentrated in vacuo. It was diluted with DMF(0.3 mL) and MeOH (2 mL) and purified by reverse phase HPLC. Theappropriate fractions were combined, basified with NaHCO₃ (solid), andconcentrated in vacuo. The residue was extracted with CH₂Cl₂ (3×). Thecombined extract was dried over MgSO₄, and concentrated in vacuo to givethe desired product (0.00758 g, 0.0144 mmol, 7.4%) as a light tan solid.LC/MS (M+H)=525.30; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 11.69 (s, 1H), 8.31(d, J=2.2 Hz, 1H), 7.89 (dd, J1=7.6, J2=1.7 Hz, 1H), 7.76 (d, J=2.2 Hz,1H), 7.61-7.66 (m, 2H), 7.54-7.59 (m, 2H), 7.50-7.54 (m, 2H), 7.47 (dd,J1=8.7 Hz, J2=1.8 Hz, 1H), 7.37 (d, J=2.2 Hz, 1H), 6.77 (dd, J1=8.9 Hz,J2=2.2 Hz, 1 H), 5.03 (d, J=16.1 Hz, 1H), 4.95 (d, J=16.6 Hz, 1H),4.15-4.19 (m, 2H), 3.69-3.74 (m, 2H), 3.33 (s, 3H), 2.44 (s, 3 H).

EXAMPLE 274-(2-Methyl-3-(4-methylbenzamido)phenyl)-6-morpholino-9H-pyrido[3,4-b]indole-1-carboxamide

1. 4-(1H-Indol-5-yl)morpholine

A heterogeneous, tan solution of 1H-indol-5-amine (4.5547 g, 34.5 mmol),1-chloro-2-(2-chloroethoxy)ethane (6.06 mL, 51.7 mmol) and Na₂CO₃ (14.61g, 138 mmol) in t-BuOH (90 mL) in a sealed pressure tube was heated to100° C. for 2 days. The reaction was cooled to room temperature, dilutedwith EtOAc and filtered through a pad of CELITE®, and the filtrate wasconcentrated in vacuo. Water (50 mL) was added to the residue andbasified to pH ˜11 with saturated aqueous NaHCO₃; this was extractedwith CH₂Cl₂ (4×75 mL). The organic layers were combined and washed withbrine, dried over MgSO₄, filtered and concentrated in vacuo to givecrude product. This was triturated with Et₂O to give the first crop ofdesired product (3.7495 g) as a tan solid. The filtrate was concentratedin vacuo, and the residue was purified by flash chromatography using anISCO 120 g column eluting with 20-50% EtOAc/hexanes to give the secondcrop of the desired product (1.9458 g).

2. Benzyl2-methyl-3-(1-(5-morpholino-1H-indol-3-yl)-2-nitroethyl)phenylcarbamate

4-(1H-Indol-5-yl)morpholine (1.102 g, 5.45 mmol) and (E)-benzyl2-methyl-3-(2-nitrovinyl)phenylcarbamate (1.2154 g, 3.89 mmol) weredissolved in THF and concentrated in vacuo to dryness. The mixture wasthen melted at 140° C. After 5 h, the reaction was cooled to roomtemperature and purified by flash chromatography using an ISCO 120 gcolumn eluting with 0-60% EtOAc/hexanes to give the desired product(0.8047 g, 1.454 mmol, 37.4% yield) as a tan foam.

3. Benzyl3-(2-amino-1-(5-morpholino-1H-indol-3-yl)ethyl)-2-methylphenylcarbamate

A solution of benzyl2-methyl-3-(1-(5-morpholino-1H-indol-3-yl)-2-nitroethyl)phenylcarbamate(0.8011 g, 1.557 mmol), ammonium chloride (1.249 g, 23.35 mmol) and zinc(1.527 g, 23.35 mmol) in methanol (32.4 mL) and tetrahydrofuran (32.4mL) was stirred for 2 hr. The reaction was filtered through a pad ofCELITE® and rinsed with methanol. The filtrate was concentrated invacuo, dissolved in EtOAc and water. The layers were separated, and theaqueous layer was extracted with EtOAc (6×). The aqueous layer wasbasified by NaHCO₃ (s) and extracted with EtOAc (3×). The organic layerswere combined, dried over MgSO₄, and concentrated in vacuo to give thedesired product (0.7121 g, 1.337 mmol, 86% yield) as a tan solid.

4. Ethyl4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-6-morpholino-9H-pyrido[3,4-b]indole-1-carboxylate

To a solution of benzyl3-(2-amino-1-(5-morpholino-1H-indol-3-yl)ethyl)-2-methylphenylcarbamate(0.713 g, 1.471 mmol) and 50% ethyl 2-oxoacetate (0.583 mL, 2.94mmol)/toluene in 1,4-dioxane (61.3 mL) was added 4 N hydrochloricacid/1,4-dioxane (0.736 mL, 2.94 mmol)/dioxane under nitrogen. Afterstirring overnight, more 50% ethyl 2-oxoacetate (0.583 mL, 2.94 mmol)was added. After 2 hr, the reaction was heated to 40° C. After another 2hr, the reaction was cooled to room temperature, concentrated in vacuo,and dissolved in water (50 mL) and EtOAc (50 mL). The mixture wasbasified with saturated NaHCO₃ solution to pH ˜10. The layers wereseparated and the aqueous layer was extracted with EtOAc (3×50 mL). Theorganic layers were combined, washed with brine, dried over MgSO₄, andconcentrated in vacuo to give crude product used in subsequent step.This was added to 10% Pd/C (0.377 g, 0.354 mmol) in p-xylene (39.4 mL),and the reaction was heated at 125° C. After 9 h, the reaction wascooled to room temperature, filtered through a wad of CELITE®, rinsedwith EtOAc, and the filtrate was concentrated in vacuo. The residue wasdissolved in EtOAc (100 mL), washed with brine (25 mL), dried overMgSO₄, and concentrated in vacuo. The residue was purified by flashchromatography using an ISCO 40 g column eluting with 0-50% EtOAc/CH₂Cl₂to give the desired product (0.1558 g, 0.276 mmol, 23.4% yield) as alight orange foam.

5.4-(3-(Benzyloxycarbonylamino)-2-methylphenyl)-6-morpholino-9H-pyrido[3,4-b]indole-1-carboxylicacid

To a light orange, homogeneous solution of ethyl4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-6-morpholino-9H-pyrido[3,4-b]indole-1-carboxylate(0.1705 g, 0.302 mmol) in methanol (3.59 mL) and THF (10.78 mL) wasadded LiOH (0.029 g, 1.208 mmol) in water (5.44 μL, 0.302 mmol). After1.5 hr, the reaction was concentrated in vacuo. Water was added to theresidue and acidified to pH ˜6 with 1 N aqueous HCl. The insolublematerial was filtered and dried over Drierite to give the desiredproduct (0.14098 g, 0.263 mmol, 87% yield) as an orange solid.

6. Benzyl3-(1-carbamoyl-6-morpholino-9H-pyrido[3,4-b]indol-4-yl)-2-methylphenylcarbamate

A solution of4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-6-morpholino-9H-pyrido[3,4-b]indole-1-carboxylicacid (0.1408 g, 0.262 mmol), ammonium chloride (0.056 g, 1.050 mmol),BOP (0.151 g, 0.341 mmol), DIPEA (0.220 mL, 1.260 mmol) andN-methylmorpholine (0.113 mL, 1.023 mmol) in DMF (2.187 mL) was stirredfor 1 hr. Water (22 mL) was added, and the precipitate was filtered,washed with water, dried over Drierite to give the desired product(0.1277 g, 0.231 mmol, 88% yield) as a light tan solid.

7.4-(3-Amino-2-methylphenyl)-6-morpholino-9H-pyrido[3,4-b]indole-1-carboxamide

A solution of benzyl3-(1-carbamoyl-6-morpholino-9H-pyrido[3,4-b]indol-4-yl)-2-methylphenylcarbamate(0.125 g, 0.233 mmol) and 10% Pd/C (0.025 g, 0.023 mmol) in methanol(8.75 mL) and THF (2.92 mL) was stirred under a hydrogen balloon. After1 hr, the reaction was flushed with nitrogen, filtered through a pad ofCELITE®, rinsed with MeOH. The filtrate was concentrated in vacuo,dissolved in CH₂Cl₂ (100 mL), dried over MgSO₄, and concentrated invacuo to give the desired product (0.0786 g, 0.196 mmol, 84% yield) as alight tan solid.

8.4-(2-Methyl-3-(4-methylbenzamido)phenyl)-6-morpholino-9H-pyrido[3,4-b]indole-1-carboxamide

To a solution of4-(3-amino-2-methylphenyl)-6-morpholino-9H-pyrido[3,4-b]indole-1-carboxamide(0.0287 g, 0.071 mmol) and 4-methylbenzoyl chloride (0.013 g, 0.086mmol) in dichloromethane (0.953 mL) under nitrogen was added pyridine(0.012 mL, 0.143 mmol). The vial was sealed and stirred at 40° C. After15 min, the reaction was cooled to room temperature and concentrated invacuo. It was diluted with MeOH (1 mL) and purified by reverse phaseHPLC. The appropriate fractions were combined, basified with NaHCO₃(solid), and concentrated in vacuo. It was extracted with CH₂Cl₂ (3×).The organic layers were combined, dried over Na₂SO₄, and concentrated invacuo to give the desired product (0.0192 g, 0.037 mmol, 51.7% yield) asa light yellow solid. LC/MS (M+H)=520.25; ¹H NMR (400 MHz, DMSO-d₆) δppm 11.56 (s, 1H), 10.00 (s, 1H), 8.31 (d, J=2.2 Hz, 1H), 8.15 (s, 1H),7.92 (s, 1H), 7.90 (s, 1H), 7.75 (d, J=2.0 Hz, 1H), 7.70 (d, J=8.80 Hz,1H), 7.55 (d, J=7.0 Hz, 1H), 7.45 (t, J=7.7 Hz, 1H), 7.35 (s, 1H), 7.33(s, 1H), 7.25-7.32 (m, 1H), 6.53 (d, J=2.2 Hz, 1H), 3.68 (m, 4H),2.80-2.91 (m, 4H), 2.38 (s, 3H), 1.94 (s, 3H).

EXAMPLE 284-(3-(4-(Dimethylamino)benzamido)-2-fluorophenyl)-7-morpholino-9H-pyrido[3,4-b]indole-1-carboxamide

1. N-(3-Cyano-2-fluorophenyl)-4-(dimethylamino)benzamide

To a mixture of 3-amino-2-fluorobenzonitrile (2.24 g, 16.46 mmol) and4-(dimethylamino)benzoyl chloride (3.46 g, 18.84 mmol) in1,2-dichloroethane (50 mL) at rt was added pyridine (0.891 mL, 11.02mmol). The resulting mixture was heated at 70° C. for 5 hr. On coolingto room temperature, the mixture was diluted with ethyl acetate (250mL), washed with water (5×60 mL) and brine (60 mL), and dried overanhydrous MgSO₄. The organic solution was concentrated under vacuum, andthe residue was subjected to ISCO (2×330 g silica gel, 25-50% ethylacetate/hexane) to afford the desired product (4.11 g, 14.51 mmol, 88%yield) as a white solid.

2. 4-(Dimethylamino)-N-(2-fluoro-3-formylphenyl)benzamide

To a solution of N-(3-cyano-2-fluorophenyl)-4-(dimethylamino)benzamide(2.18 g, 7.70 mmol) in tetrahydrofuran (150 mL) at −78° C. was addedDIBAL-H (23.09 mL, 23.09 mmol) over 20 min. The mixture was stirred at−78° C. for 1 h before it was allowed to warm to room temperature andstirred at room temperature for 4 hr. The mixture was poured intoice/water (600 mL) and stirred at room temperature for 30 min. Themixture was extracted with CH₂Cl₂ (4×100 mL). The combined extract wasfiltered through CELITE®, washed with brine (80 mL), and dried overanhydrous MgSO₄. Evaporation of the solvent under vacuum provided acrude product (1.83 g) as a pale yellow solid. This product was used inthe next step without further purification.

3. (E)-4-(Dimethylamino)-N-(2-fluoro-3-(2-nitrovinyl)phenyl)benzamide

A mixture of 4-(dimethylamino)-N-(2-fluoro-3-formylphenyl)benzamide(1.83 g, the crude product from previous step), nitromethane (0.859 mL,15.98 mmol), and ammonium acetate (1.232 g, 15.98 mmol) in acetic acid(25 mL, 52.4 mmol) was heated at 100° C. for 2 hr. Acetic acid wasremoved under vacuum. To the residue was added CH₂Cl₂ (60 mL) and water(60 mL) and the mixture was basified with solid Na₂CO₃ to pH 9. Theorganic layer was separated, and the aqueous layer was extracted withCH₂Cl₂ (3×50 mL). The combined organic phase was washed with saturatedNaHCO₃ solution (40 mL) and brine (40 mL), and dried over anhydrousMgSO₄. The desired product (0.786 g, 31% over 2 steps) was isolated byISCO (120 g silica gel, 0-5% ethyl acetate/CH₂Cl₂) as a red solid.

4.4-(Dimethylamino)-N-(2-fluoro-3-(1-(6-morpholino-1H-indol-3-yl)-2-nitroethyl)phenyl)benzamide

A mixture of 4-(1H-indol-6-yl)morpholine (0.393 g, 1.943 mmol),(E)-4-(dimethylamino)-N-(2-fluoro-3-(2-nitrovinyl)phenyl)benzamide(0.400 g, 1.215 mmol), and tris(trifluoromethylsulfonyloxy)ytterbium(0.075 g, 0.121 mmol) in acetonitrile (25 mL) was heated at 50° C. for20 h. The acetonitrile was removed under vacuum. The residue was dilutedwith ethyl acetate (180 mL), washed with 10% NaHCO₃ solution (2×40 mL)and brine (40 mL), and dried over anhydrous MgSO₄. The desired product(0.412 g, 0.750 mmol, 61.8% yield) was isolated with ISCO (80 g silicagel, 30-80% ethyl acetate/hexane) as a pale yellow solid.

5.N-(3-(2-Amino-1-(6-morpholino-1H-indol-3-yl)ethyl)-2-fluorophenyl)-4-(dimethylamino)benzamide

A mixture of4-(dimethylamino)-N-(2-fluoro-3-(1-(6-morpholino-1H-indol-3-yl)-2-nitroethyl)phenyl)benzamide(0.388 g, 0.730 mmol) and Raney Ni (a small amount) in MeOH (35 mL) wastreated with hydrogen at 55 psi a Parr shaker apparatus for 3 hr. Thecatalyst was removed by suction filtration. The filtrate wasconcentrated under vacuum, diluted with CH₂Cl₂ (100 mL), washed withbrine (25 mL) and dried over anhydrous MgSO₄. Removal of solvent undervacuum provided the desired product (0.321 g, 0.599 mmol, 82% yield) asan off-white solid.

6. Ethyl4-(3-(4-(dimethylamino)benzamido)-2-fluorophenyl)-7-morpholino-9H-pyrido[3,4-b]indole-1-carboxylate

To a solution ofN-(3-(2-amino-1-(6-morpholino-1H-indol-3-yl)ethyl)-2-fluorophenyl)-4-(dimethylamino)benzamide(0.321 g, 0.640 mmol) and ethyl 2-oxoacetate in toluene (50%) (0.279 mL,1.408 mmol) in 1,4-dioxane (30 mL) at room temperature was addedhydrogen chloride (4 N in 1,4-dioxane) (0.480 mL, 1.92 mmol). Themixture turned to heterogeneous and it was stirred room temperature for16 hr. The volatiles were removed under vacuum. The residue was dilutedwith water (30 mL), basified with NaHCO₃ solution to pH 10, andextracted with ethyl acetate (4×40 mL). The combined extract was washedwith brine (30 ml), dried over anhydrous MgSO₄, and concentrated todryness under vacuum. To the residue were added 1,4-dioxane (1 mL) andp-xylem (15 mL) and 10% Pd/C (0.4 g), and the mixture was heated at 140°C. under an ambient atmosphere for 4.5 hr. The solid phase was removedby suction filtration. The filtrate was diluted with ethyl acetate (120ml), washed with brine (25 ml), and dried over anhydrous MgSO₄. Removalof solvent under vacuum, followed by triturating with Et₂O (8 mL),provided the desired product (0.144 g, 0.238 mmol, 37.1% yield) as a tansolid.

7.4-(3-(4-(Dimethylamino)benzamido)-2-fluorophenyl)-7-morpholino-9H-pyrido[3,4-b]indole-1-carboxylicacid

To a suspension of ethyl4-(3-(4-(dimethylamino)benzamido)-2-fluorophenyl)-7-morpholino-9H-pyrido[3,4-b]indole-1-carboxylate(0.138 g, 0.237 mmol) in methanol (4 mL) at room temperature was addedsodium hydroxide (1.068 mL, 1.068 mmol). The mixture was heated atreflux for 45 min. The methanol was removed under vacuum. To the residuewas added water (5 mL), and the mixture was acidified with 1 N HCl to pH5. The insoluble product (0.110 g, 0.199 mmol, 84% yield) was collectedas a tan solid with suction filtration and dried at 50° C. under vacuum.

8.4-(3-(4-(Dimethylamino)benzamido)-2-fluorophenyl)-7-morpholino-9H-pyrido[3,4-b]indole-1-carboxamide

A mixture of4-(3-(4-(dimethylamino)benzamido)-2-fluorophenyl)-7-morpholino-9H-pyrido[3,4-b]indole-1-carboxylicacid (105 mg, 0.190 mmol), ammonium chloride (40.6 mg, 0.759 mmol),N,N-diisopropylethylamine (0.159 mL, 0.910 mmol), BOP (109 mg, 0.247mmol), N-methylmorpholine (0.081 mL, 0.740 mmol) in DMF (0.5 mL) wasstirred at room temperature for 1.5 hr. The mixture was diluted withMeOH (4 mL), divided into three portions, and purified by reverse phaseHPLC. The correct fractions were concentrated under vacuum and basifiedwith saturated NaHCO₃ solution to pH 10. The precipitating product (24.7mg, 0.044 mmol, 23.09% yield) was collected as a yellow solid by suctionfiltration and dried at 50° C. under vacuum. LCMS (M+H)⁺=553.32. ¹H NMR(500 z, DMSO-d₆) δ: 11.52 (s, 1H), 9.86 (s, 1H), 8.31 (s, 1H), 8.20 (s,1H), 7.90 (d, J=9.0 Hz, 2H), 7.84 (m, 1H), 7.76 (s, 1H), 7.45-7.40 (m,2H), 7.32 (d, J=8.0 Hz, 1H), 7.29 (d, J=2.0 Hz, 1H), 6.86 (dd, J1=9.0Hz, J2=2.0 Hz, 1H), 6.77 (d, J=9.0 Hz, 2H), 3.79-3.77 (m, 4H), 3.22-3.19(m, 4H), 2.51 (m, 6H).

EXAMPLE 297-(2-Hydroxypropan-2-yl)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide

1. Benzyl3-(1-(6-bromo-1H-indol-3-yl)-2-nitroethyl)-2-methylphenylcarbamate

A mixture of 6-bromo-1H-indole (2.82 g, 14.41 mmol) and (E)-benzyl2-methyl-3-(2-nitrovinyl)phenylcarbamate (3.0 g, 9.61 mmol) wasdissolved in THF (50 mL) and NMP (0.5 mL). The THF was removed undervacuum, and the residue was heated at 120° C. for 16 hr and then at 125°C. for 6 hr. Upon cooling to room temperature, the mixture was dissolvedin THF (50 mL). The resulting solution was diluted with ethyl acetate(250 mL), washed with water (3×80 mL) and brine (60 mL), and dried overanhydrous MgSO₄. The desired product (3.00 g, 5.90 mmol, 61.4% yield)was isolated as a beige solid by ISCO (300 g silica gel, 25-60 ethylacetate/hexane).

2. Benzyl3-(2-amino-1-(6-bromo-1H-indol-3-yl)ethyl)-2-methylphenylcarbamate

To a mixture of benzyl3-(1-(6-bromo-1H-indol-3-yl)-2-nitroethyl)-2-methylphenylcarbamate (3.00g, 5.90 mmol) and ammonium chloride (4.42 g, 83 mmol) in methanol (100mL) and tetrahydrofuran (100 mL) at 0° C. was added zinc dust (5.40 g,83 mmol) in one portion. The mixture was stirred at room temperature for7 hr, then diluted with ethyl acetate (100 mL) and filtered throughCELITE®. The filtrate was concentrated under vacuum. To the residue wasadded water (60 mL), and the mixture was extracted with ethyl acetate(4×80 mL). The combined extract was washed with brine (60 mL) and driedover anhydrous MgSO₄. Removal of solvent under vacuum provided thedesired product (2.82 g, 5.89 mmol, 100% yield) as a beige solid.

3. Ethyl4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-7-bromo-9H-pyrido[3,4-b]indole-1-carboxylate

To a mixture of benzyl3-(2-amino-1-(6-bromo-1H-indol-3-yl)ethyl)-2-methylphenylcarbamate(2.320 g, 4.85 mmol) and 4 angstrom molecular sieves (powder, activated,<5 mesh, 1.80 g) in tetrahydrofuran (100 mL) at room temperature wasadded ethyl 2-oxoacetate in toluene (1.923 mL, 9.70 mmol), followed byhydrogen chloride in 1,4-dioxane (1.334 mL, 5.33 mmol). The mixture wasstirred at room temperature for 24 h. The solid phase was removed bysuction filtration through CELITE®, and the filtrate was concentratedunder vacuum. The residue was diluted with water (60 mL), basified withsaturated NaHCO₃ solution, and extracted with ethyl acetate (3×80 mL).The combined extract was washed with brine (60 mL) and dried overanhydrous MgSO₄. The solvent was removed under vacuum. To the residuewas added p-xylene (200 mL) and 10% Pd/C (1.5 g), and the mixture washeated under atmosphere at 125° C. for 16 hr. The solid phase wasremoved by suction filtration through CELITE®. The filtrate wasconcentrated under vacuum, and the residue was purified by ISCO (220 gsilica gel, solid loading, 20-50% ethyl acetate/hexane) to provide thedesired product (0.977 g, 36% yield) as a beige solid.

4.4-(3-(Benzyloxycarbonylamino)-2-methylphenyl)-7-bromo-9H-pyrido[3,4-b]indole-1-carboxylicacid

To a solution of ethyl4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-7-bromo-9H-pyrido[3,4-b]indole-1-carboxylate(1.338 g, 2.396 mmol) in tetrahydrofuran (48 mL) and methanol (16 mL) atroom temperature was added a solution of lithium hydroxide hydrate(0.402 g, 9.58 mmol) in water (10 mL). The resulting solution wasstirred at room temperature for 1.5 hr, and then concentrated undervacuum to a volume of about 10 mL. The residue was diluted with water (5mL) and neutralized with 1 N HCl solution to pH 5-6. The precipitatingproduct (1.177 g, 2.219 mmol, 93% yield) was collected as a beige solidby suction filtration and dried over Drierite under vacuum.

5. Benzyl3-(7-bromo-1-carbamoyl-9H-pyrido[3,4-b]indol-4-yl)-2-methylphenylcarbamate

A mixture of4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-7-bromo-9H-pyrido[3,4-b]indole-1-carboxylicacid (1.174 g, 2.214 mmol), ammonium chloride (0.474 g, 8.85 mmol),N,N-diisopropylethylamine (1.856 mL, 10.63 mmol), BOP (1.273 g, 2.88mmol), and N-methylmorpholine (0.949 mL, 8.63 mmol) in DMF (Volume: 10mL) was stirred at room temperature for 2 hr. To the mixture was addedwater (120 mL), and the resulting mixture was stirred at roomtemperature for 20 min. The precipitating product (1.23 g) was collectedas a beige solid by suction filtration and dried over Drierite at 50° C.This product was 80% pure, but was used in the next step without furtherpurification.

6.4-(3-Amino-2-methylphenyl)-7-bromo-9H-pyrido[3,4-b]indole-1-carboxamide

To a solution of benzyl3-(7-bromo-1-carbamoyl-9H-pyrido[3,4-b]indol-4-yl)-2-methylphenylcarbamate(0.65 g, crude from the previous step) in acetonitrile (80 mL) at 0° C.was added iodotrimethylsilane (0.67 mL, 4.91 mmol) dropwise. The mixturewas stirred at room temperature for 1.5 hr, and then concentrated undervacuum. To the residue was added diethylamine (2 mL) and ethyl acetate(150 ml). The mixture was washed with water (2×40 mL) and brine (40 mL),and dried over anhydrous MgSO₄. The desired product (0.243 g, 52.6%yield over two steps) was isolated as a beige solid by ISCO (40 g silicagel, solid loading, 40-70% ethyl acetate/hexane).

7.7-Bromo-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide

A mixture of4-(3-amino-2-methylphenyl)-7-bromo-9H-pyrido[3,4-b]indole-1-carboxamide(0.243 g, 0.615 mmol), 1H-benzo[d][1,3]oxazine-2,4-dione (0.251 g, 1.537mmol), tris(nitrooxy)lanthanum, 6H₂O (0.080 g, 0.184 mmol), andtrimethoxymethane (2.020 mL, 18.44 mmol) in tetrahydrofuran (2 mL) washeated at 90° C. for 16 hr. The mixture was diluted with ethyl acetate(120 mL), washed with water (2×30 mL) and brine (30 mL), and dried overanhydrous MgSO₄. The desired product (0.198 g, 0.378 mmol, 61.4% yield)was isolated as a yellow solid by ISCO (40 g silica gel, solid loading,40-80% ethyl acetate/hexane).

8.7-Acetyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide

A mixture of7-bromo-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide(0.198 g, 0.378 mmol), tributyl(1-ethoxyvinyl)stannane (0.299 mL, 0.906mmol), bis(triphenylphosphine)palladium(II) chloride (0.037 g, 0.053mmol), triethylamine (0.068 mL, 0.491 mmol) in 1,4-dioxane (Volume: 15mL) was heated at 95° C. for 24 hr. No reaction occurred. The startingbromo compound remained unchanged. Upon cooling to room temperature,some yellow precipitate formed. The clear solution was transferred to apressure tube. Additional tributyl(1-ethoxyvinyl)stannane (0.6 mL, 1.82mmol), bis(triphenylphosphine)palladium(II) chloride (0.080 g, 0.114mmol), and triethylamine (0.11 mL, 0.789 mmol) were added. The mixturewas heated at 125° C. for 16 hr. Upon cooling to room temperature, thereaction mixture was filtered through CELITE®, and the filtrate wasconcentrated under vacuum. The residue was diluted with THF (30 mL) andstirred with 1 N HCl solution (10 mL) at room temperature for 2 hr. Thesolution was concentrated under vacuum, basified with 1 N NaOH solution,and extracted with ethyl acetate (3×40 mL). The combined extract wasdried over anhydrous MgSO₄. The desired product (90 mg, 0.185 mmol,48.9% yield) was isolated as a yellow solid by ISCO (24 g silica gel,solid loading, 60-90% ethyl acetate/hexane).

9.7-(2-Hydroxypropan-2-yl)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide

To a solution of7-acetyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide(45 mg, 0.092 mmol) in tetrahydrofuran (10 mL) at 0° C. was addedmethylmagnesium bromide (0.154 mL, 0.462 mmol). The mixture was stirredat room temperature for 30 min. Additional methylmagnesium bromide(0.100 mL, 0.300 mmol) was added at 0° C., and the mixture was stirredat room temperature for another 30 min. The reaction was quenched withwater (10 mL) and the mixture was extracted with ethyl acetate (3×30mL). The combined extract was washed with brine (25 mL) and dried overanhydrous MgSO₄. The organic solution was concentrated under vacuum, andthe residue was purified by reverse phase HPLC. The correct fraction wasconcentrated under vacuum, basified with saturated NaHCO₃ solution, andextracted with ethyl acetate (3×35 mL). The combined extract was washedwith brine (30 mL) and dried over anhydrous MgSO₄. Removal of solventunder vacuum provided the desired product (20.9 mg, 0.041 mmol, 44.1%yield) as a pale yellow solid. LCMS (M+H)⁺=504.0. ¹H NMR (500 MHz,DMSO-d₆) (recognizable peaks for the major atropisomer) δ: 11.74 (s,1H), 8.44 (s, 1H), 8.23 (s, 1H), 8.30 (s, 1H), 7.98 (m, 1H), 7.92 (m,1H), 7.80 (m, 1H), 7.75 (m, 1H), 7.58 (m, 1H), 7.24 (m, 1H), 5.12 (s,1H), 1.83 (s, 3H), 1.50 (s, 6H).

EXAMPLE 307-(1-Hydroxyethyl)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide

To a cloudy solution of7-acetyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide(45 mg, 0.092 mmol) in tetrahydrofuran (4 mL) and methanol (12 mL) at 0°C. was added sodium borohydride (17.46 mg, 0.462 mmol) in one portion.The mixture was stirred at room temperature for 20 min and then thereaction was quenched with ice cold water (15 mL). The resulting mixturewas extracted with ethyl acetate (3×30 mL). The combined extract waswashed with brine (25 mL) and dried over anhydrous MgSO₄. The organicsolution was concentrated under vacuum, and the residue was purified byreverse phase HPLC. The correct fraction was concentrated under vacuum,basified with saturated NaHCO₃ solution, and extracted withdichloromethane (3×35 mL). The combined extract was washed with brine(30 mL) and dried over anhydrous MgSO₄. Removal of solvent under vacuumprovided the desired product (10.9 mg, 0.022 mmol, 23.5% yield) as awhite solid. LCMS (M+H)⁺=490.1. ¹H NMR (500 MHz, DMSO-d₆) (recognizablepeaks for the major atropisomer) δ: 11.78 (s, 1H), 8.44 (s, 1H), 8.30(s, 1H), 8.28 (dd, J1=8.0 Hz, J2=1.4 Hz, 1H), 8.25 (s, 1H), 8.24 (s,1H), 7.30 (m, 1H), 7.12 (m, 1H), 5.25 (s, 1H), 4.85 (m, 1H), 1.82 (s,3H),

EXAMPLE 317-(1-Hydroxyethyl)-4-(3-(6-methoxy-1-oxoisoindolin-2-yl)-2-methylphenyl)-9H-pyrido[3,4-b]indole-1-carboxamide

1.2-((3-(7-Bromo-1-carbamoyl-9H-pyrido[3,4-b]indol-4-yl)-2-methylphenylamino)methyl)-5-methoxybenzoicacid

A mixture of4-(3-amino-2-methylphenyl)-7-bromo-9H-pyrido[3,4-b]indole-1-carboxamide(0.184 g, 0.466 mmol), 2-formyl-5-methoxybenzoic acid (0.210 g, 1.164mmol), sodium triacetoxyborohydride (0.296 g, 1.397 mmol), and aceticacid (0.067 mL, 1.164 mmol) in dichloromethane (14 mL) andtetrahydrofuran (14 mL) was stirred at room temperature for 16 hr. Thereaction was quenched with water (30 mL) and the mixture was extractedwith ethyl acetate (3×40 mL). The combined extract was washed with brine(30 ml) and dried over anhydrous MgSO₄. Removal of solvent under vacuumprovided the crude desired product (0.425 g, 0.760 mmol, 163% yield) asa beige solid. The crude product was used in the next step withoutfurther purification.

2.7-Bromo-4-(3-(6-methoxy-1-oxoisoindolin-2-yl)-2-methylphenyl)-9H-pyrido[3,4-b]indole-1-carboxamide

A mixture of2-((3-(7-bromo-1-carbamoyl-9H-pyrido[3,4-b]indol-4-yl)-2-methylphenylamino)methyl)-5-methoxybenzoicacid (0.425 g, the crude product from the previous step), BOP (1.008 g,2.279 mmol), and N-methylmorpholine (0.752 mL, 6.84 mmol) in DMF(Volume: 5 mL) was stirred at 50° C. for 1 hr. The mixture was dilutedwith ethyl acetate (100 mL), washed with water (2×25 mL) and brine (25mL), and dried over anhydrous MgSO₄. The desired product (0.198 g, 78%yield over 2 steps), was isolated as a yellow solid by ISCO (40 g silicagel, solid loading, 40-80% ethyl acetate/hexane).

3.7-Acetyl-4-(3-(6-methoxy-1-oxoisoindolin-2-yl)-2-methylphenyl)-9H-pyrido[3,4-b]indole-1-carboxamide

A mixture of7-bromo-4-(3-(6-methoxy-1-oxoisoindolin-2-yl)-2-methylphenyl)-9H-pyrido[3,4-b]indole-1-carboxamide(0.198 g, 0.366 mmol), tributyl(1-ethoxyvinyl)stannane (0.301 mL, 0.914mmol), bis(triphenylphosphine)palladium(II) chloride (0.039 g, 0.055mmol), triethylamine (0.071 mL, 0.512 mmol) in 1,4-Dioxane (12 mL) washeated at 125° C. for 16 hr. Upon cooling to room temperature, thereaction mixture was filtered through CELITE®, and the filtrate wasconcentrated under vacuum. The residue was diluted with THF (40 mL) andstirred with 1 N HCl solution (10 mL) at 50° C. for 1 hr. The solutionwas concentrated under vacuum, basified with 1 N NaOH solution, andextracted with ethyl acetate (3×40 mL). The combined extract was driedover anhydrous MgSO₄. The desired product (0.112 g, 0.222 mmol, 60.7%yield) was isolated as a pale yellow solid by ISCO (40 g silica gel,solid loading, 50-90% ethyl acetate/hexane).

4.7-(1-Hydroxyethyl)-4-(3-(6-methoxy-1-oxoisoindolin-2-yl)-2-methylphenyl)-9H-pyrido[3,4-b]indole-1-carboxamide

To a cloudy solution of7-acetyl-4-(3-(6-methoxy-1-oxoisoindolin-2-yl)-2-methylphenyl)-9H-pyrido[3,4-b]indole-1-carboxamide(62 mg, 0.123 mmol) in tetrahydrofuran (5 mL) and methanol (15 mL) at 0°C. was added sodium borohydride (23.25 mg, 0.614 mmol) in one portion.The mixture was stirred at room temperature for 30 min and then thereaction was quenched with ice cold water (15 mL). The resulting mixturewas extracted with ethyl acetate (3×30 mL). The combined extract waswashed with brine (25 mL) and dried over anhydrous MgSO₄. The organicsolution was concentrated under vacuum, and the residue was purified byreverse phase HPLC. The correct fraction was concentrated under vacuum,basified with saturated NaHCO₃ solution, and extracted withdichloromethane (3×35 mL). The combined extract was washed with brine(30 mL) and dried over anhydrous MgSO₄. Removal of solvent under vacuumprovided the desired product (24.8 mg, 0.047 mmol, 38.6% yield) as awhite solid. LCMS (M+H)⁺=507.24. ¹H NMR (500 MHz, DMSO-d₆) δ: 11.77 (s,1H), 8.32 (s, 1H), 8.23 (s, 1H), 7.83 (d, J=11.6 Hz, 1H), 7.75 (s, 1H),7.67 (d, J=6.9 Hz, 1H), 7.60 (d, J=8.3 Hz, 1H), 7.54 (m, 1H), 7.43 (d,J=7.5 Hz, 1H), 7.32 (m, 1H), 7.27-7.23 (m, 2H), 7.08 (dd, J1=12.9 Hz,J2=8.5 Hz, 1H), 5.26 (m, 1H), 4.85 (m, 1H), 4.96 (d, J=16.9 Hz, 1H),4.86 (d, J=16.9 Hz, 1H), 3.86 (s, 3H), 1.88 (s, 3H), 1.38 (d, J=6.4 Hz,3H).

EXAMPLE 321-(3-(6-Chloro-1-oxoisoindolin-2-yl)-2-methylphenyl)-7-(2-methoxyethoxy)-5H-pyridazino[4,5-b]indole-4-carboxamide

1. Methyl 6-(2-methoxyethoxy)-1H-indole-2-carboxylate

To a light brown, homogeneous solution of methyl6-hydroxy-1H-indole-2-carboxylate (1.4862 g, 7.77 mmol) and1-bromo-2-methoxyethane (0.731 mL, 7.77 mmol) in DMF (38.9 mL) undernitrogen was added cesium carbonate (2.53 g, 7.77 mmol). The reactionwas heated to 55° C. and stirred overnight. The reaction was cooled toroom temperature, diluted with EtOAc (200 mL) and filtered throughCELITE®. The filtrate was washed with water (4×50 mL) and brine (2×50mL), dried over MgSO₄, and concentrated in vacuo to give a residue whichwas purified by flash chromatography using an ISCO 120 g column elutingwith 20-60% EtOAc/hexanes. Appropriate fractions were collected andconcentrated in vacuo to give desired product (0.8592 g) as a whitesolid. Mixed fractions were combined and concentrated in vacuo to give aresidue which was purified by flash chromatography using an ISCO 80 gcolumn eluting with 20-60% EtOAc/hexanes to give another crop of desiredproduct (0.1673 g) as a white solid.

2. Methyl6-(2-methoxyethoxy)-3-(2-methyl-3-nitrobenzoyl)-1H-indole-2-carboxylate

To a homogeneous, colorless solution of methyl6-(2-methoxyethoxy)-1H-indole-2-carboxylate (0.934 g, 3.75 mmol) indichloromethane (18.74 mL) at 0° C. under nitrogen was added 1Mperchlorostannane/CH₂Cl₂ (4.87 mL, 4.87 mmol) over 10 min. After 5 min,the cold bath was removed, and the yellow, heterogeneous solution wasstirred to room temperature for 30 min. A solution of2-methyl-3-nitrobenzoyl chloride (0.897 g, 4.50 mmol) in nitromethane(18.74 mL, previously dried over MgSO₄ overnight) was added over 20 min.After 3.25 hr, additional acid chloride (0.350 g) in nitromethane (3 mL)was added to the reaction. Thirty minutes later, the reaction was pouredinto ice water (50 mL) and stirred for 15 min. It was diluted with EtOAc(150 mL) and washed with water (50 mL), sat. aq. NaHCO₃ (50 mL) andbrine (25 mL). The organic solution was dried over MgSO₄ andconcentrated in vacuo to give the desired product (1.6103 g, 3.90 mmol,104% yield) as a solid.

3.7-(2-Methoxyethoxy)-1-(2-methyl-3-nitrophenyl)-3H-pyridazino[4,5-b]indol-4(5H)-one

A yellow, homogeneous solution of methyl6-(2-methoxyethoxy)-3-(2-methyl-3-nitrobenzoyl)-1H-indole-2-carboxylate(1.546 g, 3.75 mmol) and hydrazine hydrate (0.982 mL, 13.13 mmol) inethanol (55.1 mL) under nitrogen was refluxed overnight. The reactionwas cooled to room temperature and concentrated in vacuo. It wasdissolved in EtOAc (150 mL) and washed with water (40 mL) and brine (40mL), dried over MgSO₄, and concentrated in vacuo to give a residue whichwas purified by flash chromatography using an ISCO 120 g column elutingwith 0-100% EtOAc/hexanes. Appropriate fractions were collected andconcentrated in vacuo to give the desired product (0.7461 g, 1.892 mmol,50.4% yield) as a light yellow solid.

4.4-Chloro-7-(2-methoxyethoxy)-1-(2-methyl-3-nitrophenyl)-5H-pyridazino[4,5-b]indole

A yellow, homogeneous solution of7-(2-methoxyethoxy)-1-(2-methyl-3-nitrophenyl)-3H-pyridazino[4,5-b]indol-4(5H)-one(0.2510 g, 0.636 mmol) in phosphoryl trichloride (20 mL, 0.636 mmol)under nitrogen was heated at 100° C. After 1 h, the reaction was cooledto room temperature and concentrated in vacuo. The residue was dissolvedin cold EtOAc (250 mL) and was with ice-cold water (40 mL), ice-coldsaturated aqueous NaHCO₃ (40 mL), ice-cold water (40 mL) and ice-coldbrine (40 mL), successively. The organic solution was dried over MgSO₄and concentrated in vacuo to give the desired product (0.2115 g, 0.512mmol, 80% yield) as a light orange solid.

5. Methyl1-(3-amino-2-methylphenyl)-7-(2-methoxyethoxy)-5H-pyridazino[4,5-b]indole-4-carboxylate

A steel bomb containing a solution of4-chloro-7-(2-methoxyethoxy)-1-(2-methyl-3-nitrophenyl)-5H-pyridazino[4,5-b]indole(0.5862 g, 1.420 mmol), DPPF (0.118 g, 0.213 mmol), palladium(II)acetate (0.048 g, 0.213 mmol) and sodium acetate (0.233 g, 2.84 mmol) inDMA (10 mL) and methanol (20 mL, 494 mmol) was evacuated and flushedwith nitrogen twice. It was then evacuated, filled with CO (g) to 70 psiand heated at 90° C. overnight. The oil bath was removed, and the bombwas cooled to room temperature followed by immersion in dry ice; valvewas then released. The cold bath was removed, and the reaction waswarmed to room temperature. The solution was filtered through a pad ofCELITE® and rinsed with MeOH. The filtrate was concentrated in vacuo,diluted with EtOAc (200 mL) and saturated aqueous NaHCO₃ (40 mL). Afterseparation of the layers, the organic layer was washed with brine (40mL), dried over MgSO₄, and concentrated in vacuo to give the desiredproduct (0.600 g, 1.476 mmol, 104% yield) as a light burgundy solid.

6.5-Chloro-2-((3-(4-(methoxycarbonyl)-7-(2-methoxyethoxy)-5H-pyridazino[4,5-b]indol-1-yl)-2-methylphenylamino)methyl)benzoicacid

To a homogeneous, burgundy solution of methyl1-(3-amino-2-methylphenyl)-7-(2-methoxyethoxy)-5H-pyridazino[4,5-b]indole-4-carboxylate(0.1603 g, 0.394 mmol), 5-chloro-2-formylbenzoic acid (0.182 g, 0.986mmol) and acetic acid (0.056 mL, 0.986 mmol) in dichloromethane (7.89mL) and tetrahydrofuran (5.26 mL) under nitrogen was added sodiumtriacetoxyborohydride (0.251 g, 1.183 mmol), and the reaction wasstirred overnight. More sodium triacetoxyborohydride (146.2 mg) wasadded. After 1 hr, water (6 mL) was added, and the reaction was stirredfor 30 min. It was dissolved in EtOAc (100 mL) and washed with water(3×30 mL) and brine (30 mL), dried over MgSO₄, and concentrated in vacuoto give a crude product, which was used in the subsequent step.

7. Methyl1-(3-(6-chloro-1-oxoisoindolin-2-yl)-2-methylphenyl)-7-(2-methoxyethoxy)-5H-pyridazino[4,5-b]indole-4-carboxylate

A solution of5-chloro-2-((3-(4-(methoxycarbonyl)-7-(2-methoxyethoxy)-5H-pyridazino[4,5-b]indol-1-yl)-2-methylphenylamino)methyl)benzoic acid (0.227 g,0.394 mmol), BOP (0.366 g, 0.827 mmol), and N-methylmorpholine (0.273mL, 2.482 mmol) in DMF (3.94 mL) under nitrogen was heated at 45° C.After 6 hr, the reaction was cooled to room temperature, dissolved inEtOAc (100 mL) and washed with water (3×25 mL) and brine (25 mL), driedover MgSO₄, filtered and concentrated in vacuo to give a residue whichwas purified by flash chromatography using an ISCO 24 g column elutingwith 0-5% MeOH/CH₂Cl₂. Appropriate fractions were collected andconcentrated in vacuo to give the desired product (0.0384 g, 0.069 mmol,17.5% yield) as a light orange solid.

8.1-(3-(6-Chloro-1-oxoisoindolin-2-yl)-2-methylphenyl)-7-(2-methoxyethoxy)-5H-pyridazino[4,5-b]indole-4-carboxylicacid

To a yellow, homogeneous solution of methyl1-(3-(6-chloro-1-oxoisoindolin-2-yl)-2-methylphenyl)-7-(2-methoxyethoxy)-5H-pyridazino[4,5-b]indole-4-carboxylate (0.05 g, 0.090 mmol) in THF (1.924 mL) andMeOH (0.641 mL) was added a solution of lithium hydroxide hydrate (0.015g, 0.359 mmol) in water (0.5 mL). After 2.25 hr, the reaction wasconcentrated in vacuo, acidified with aqueous 1 N HCl to pH ˜4-5 bylitmus paper. The precipitate was filtered and dried over Drierite togive the desired product (0.0206 g, 0.038 mmol, 42.3% yield) as a lighttan solid.

9.1-(3-(6-Chloro-1-oxoisoindolin-2-yl)-2-methylphenyl)-7-(2-methoxyethoxy)-5H-pyridazino[4,5-b]indole-4-carboxamide

A yellow, homogeneous solution of1-(3-(6-chloro-1-oxoisoindolin-2-yl)-2-methylphenyl)-7-(2-methoxyethoxy)-5H-pyridazino[4,5-b]indole-4-carboxylicacid (0.0206 g, 0.038 mmol), ammonium chloride (8.12 mg, 0.152 mmol),DIPEA (0.032 mL, 0.182 mmol), N-methylmorpholine (5.42 μL, 0.049 mmol)and BOP (0.065 g, 0.148 mmol) in DMF (0.379 mL) was stirred for 1 hr. Itwas diluted with MeOH (1 mL) and purified by reverse phase HPLC. Theappropriate fractions were collected, basified with NaHCO₃ (solid), andconcentrated in vacuo. The residue was extracted with CH₂Cl₂ (3×). Thecombined extract was dried over Na₂SO₄ and concentrated in vacuo to givethe desired product (0.0064 g, 0.012 mmol, 30.9% yield) as a whitesolid. LC/MS (M+H)=542.15; ¹H NMR (500 MHz, DMSO-d₆) (recognizable peaksfor major atropoisomer) δ ppm 12.22 (s, 1H), 8.71 (s, 1H), 7.98 (s, 1H),7.80-7.85 (m, 1H), 7.74-7.76 (m, 2H), 7.73 (d, J=1.1 Hz, 1H), 7.58 (s,1H), 7.53 (d, J=1.1 Hz, 1H), 7.41 (d, J=2.2 Hz, 1H), 7.19 (d, J=8.9 Hz,1H), 6.87 (d, J=2.2 Hz, 1H), 5.05 (d, J=17.8 Hz, 1H), 4.98 (d, J=17.5Hz, 1H), 4.14-4.21 (m, 2H), 3.72 (dd, J1=5.4 Hz, J2=3.8 Hz, 2H), 3.32(s, 3 H), 1.88 (s, 3 H).

EXAMPLE 337-(2-Methoxyethoxy)-1-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-5H-pyridazino[4,5-b]indole-4-carboxamide

1. Methyl1-(3-amino-2-methylphenyl)-7-(2-methoxyethoxy)-5H-pyridazino[4,5-b]indole-4-carboxylate

A sealed pressure tube containing methyl1-(3-amino-2-methylphenyl)-7-(2-methoxyethoxy)-5H-pyridazino[4,5-b]indole-4-carboxylate(0.2838 g, 0.698 mmol) in 7N NH₃/MeOH (5.0 mL, 35.0 mmol) was heated at100° C. for 6.5 hr. After cooling to room temperature, the reaction wasstirred without the cap for 20 min and concentrated in vacuo to give thedesired product (0.316 g, 0.807 mmol, 116% yield) as a dark solid.

2.7-(2-Methoxyethoxy)-1-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-5H-pyridazino[4,5-b]indole-4-carboxamide

A sealed pressure tube containing1-(3-amino-2-methylphenyl)-7-(2-methoxyethoxy)-5H-pyridazino[4,5-b]indole-4-carboxamide(0.2785 g, 0.712 mmol), trimethoxymethane (0.701 mL, 6.40 mmol),1H-benzo[d][1,3]oxazine-2,4-dione (0.232 g, 1.423 mmol), and lanthanumnitrate hexahydrate (0.092 g, 0.213 mmol) in tetrahydrofuran (3.56 mL)was heated at 95° C. for 6 hr and cooled to room temperature. EtOAc (100mL) was added, and the resulting mixture was washed with water (20 mL),1N aq. NaOH (20 mL), water (20 mL) and brine (20 mL) successively. Itwas then dried over MgSO₄ and concentrated in vacuo to give a residuewhich was purified by flash chromatography using an ISCO 24 g columneluting with 1-10% MeOH/CH₂Cl₂ to give crude product. This crude wasdissolved in DMSO (0.2 mL) and MeOH (0.6 mL) and purified by reversephase HPLC. The appropriate fractions were collected, basified withNaHCO₃ (solid), and concentrated in vacuo. The residue was extractedwith CH₂Cl₂ (3×). The combined extract was dried over Na₂SO₄ andconcentrated in vacuo to give (0.0163 g, 0.031 mmol, 4.4% yield) as alight yellow solid. LC/MS (M+H)=521.18; ¹H NMR (500 MHz, DMSO-d₆)(recognizable peaks for the major atropoisomer) δ ppm 12.24 (s, 1H),8.76 (br. S, 1H), 8.71 (br. S, 1H), 8.53 (s, 1H), 8.48 (s, 1H), 8.26 (t,J=6.9 Hz, 1H), 8.00 (br. S, 1H), 7.89-7.94 (m, 1H), 7.80 (s, 1H), 7.74(d, J=5.6 Hz, 1H), 7.60-7.70 (m, 2H), 7.41 (d, J=2.2 Hz, 1H), 6.88 (d,J=8.9 Hz, 1H), 4.15-4.21 (m, 2H), 3.72 (t, J=4.3 Hz, 2 H), 3.33 (s, 3H),1.81 (s, 3H).

EXAMPLE 347-(2-Hydroxyethoxy)-1-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-5H-pyridazino[4,5-b]indole-4-carboxamide

To a homogeneous, light orange solution of7-(2-methoxyethoxy)-1-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-5H-pyridazino[4,5-b]indole-4-carboxamide(0.0973 g, 0.155 mmol) in dichloromethane (5 ml) under nitrogen at 0° C.was added 1M tribromoborane/dichoromethane (0.496 ml, 0.496 mmol) over 5min. After 5 min, the cold bath was removed, and the heterogeneoussolution was stirred to room temperature. One hour later, the reactionwas immersed in an ice-water bath and ice water (15 mL) was added. Theresulting mixture was basified with 1 N aqueous NaOH solution to pH ˜10by litmus paper. EtOAc (50 mL) was added, and the layers were separated.The aqueous layer was extracted with EtOAc (2×50 mL). The combinedextract was dried over MgSO₄ and concentrated in vacuo to give a residuewhich was diluted with MeOH (1 mL) and purified by reverse phase HPLC.The appropriate fractions were collected, basified with NaHCO₃ (solid),and concentrated in vacuo. The residue was extracted with CH₂Cl₂ (3×).The combined extract was dried over Na₂SO₄ and concentrated in vacuo togive the desired product (0.0148 g, 0.029 mmol, 18.8% yield) as a lightyellow solid. LC/MS (M+H)=507.21; ¹H NMR (500 MHz, DMSO-d₆)(recognizable peaks for the major atropoisomer) δ ppm 12.23 (s, 1H),8.71 (br. S, 1H), 8.48 (s, 1H), 8.26 (t, J=6.2 Hz, 1H), 8.00 (br. S,1H), 7.88-7.94 (m, 1H), 7.79 (d, J=8.0 Hz, 1H)), 7.72-7.77 (m, 1H),7.58-7.70 (m, 3H), 7.41 (d, J=2.2 Hz, 1H), 7.29 (d, J=8.6 Hz, 1H), 6.88(dd, J1=8.9, J2=2.2 Hz, 1H), 4.84-4.97 (m, 1H), 4.01-4.14 (m, 2H),3.71-3.85 (m, 2H), 1.81 (s, 3H).

EXAMPLE 357-Acetyl-1-(3-(6-methoxy-1-oxoisoindolin-2-yl)-2-methylphenyl)-5H-pyridazino[4,5-b]indole-4-carboxamide

1. Ethyl 6-bromo-3-(2-methyl-3-nitrobenzoyl)-1H-indole-2-carboxylate

To a solution of ethyl 6-bromo-1H-indole-2-carboxylate (4.40 g, 16.41mmol) in dichloromethane (70 mL) at 0° C. was added tin (IV) chloride indichloromethane (20.51 mL, 20.51 mmol) over 15 min. The resulting yellowheterogeneous mixture was stirred at room temperature for 30 min beforea solution 2-methyl-3-nitrobenzoyl chloride (4.42 g, 22.16 mmol) innitromethane (70 mL) was added over 20 min. The mixture was stirred atroom temperature for 4 hr and then poured into ice-cold water (200 mL).The resulting mixture was stirred at room temperature for 20 min anddiluted with ethyl acetate (800 ml). The mixture was washed with water(100 mL), saturated NaHCO₃ solution (2×100 ml), water (100 mL), andbrine (100 mL). The organic solution was dried over anhydrous MgSO₄.Removal of solvent under vacuum gave the desired product (7.04 g, 16.33mmol, 99% yield) as yellow solid.

2.7-Bromo-1-(2-methyl-3-nitrophenyl)-3H-pyridazino[4,5-b]indol-4(5H)-one

A solution of ethyl6-bromo-3-(2-methyl-3-nitrobenzoyl)-1H-indole-2-carboxylate (6.02 g,13.96 mmol) and hydrazine hydrate (2.446 g, 48.9 mmol) in ethanol (200mL) was heated at reflux for 16 hr. The mixture was concentrated undervacuum to a volume of approximate 30 mL. The insoluble product (4.56 g,11.42 mmol, 82% yield) was collected by suction filtration and driedunder vacuum at 50° C.

3.7-Acetyl-1-(2-methyl-3-nitrophenyl)-3H-pyridazino[4,5-b]indol-4(5H)-one

A mixture of 7-bromo-1-(2-methyl-3-nitrophenyl)-3H-pyridazino[4,5-b]indol-4(5H)-one (2.00 g, 5.01 mmol),tributyl(1-ethoxyvinyl)stannane (4.06 mL, 12.02 mmol),dichlorobis(triphenylphosphine)-palladium(II) (0.422 g, 0.601 mmol), andtriethylamine (0.908 mL, 6.51 mmol) in 1,4-Dioxane (100 mL) was heatedat 95° C. for 24 hr. Upon cooling to room temperature, the mixture wasfiltered through CELITE®. The filtrate was concentrated under vacuum todryness. To the residue was added THF (100 mL) and 1 N HCl solution (100mL), and the mixture was stirred at 60° C. for 1.5 hr. It wasconcentrated under vacuum to a volume of 100 mL, neutralized with 1 NNaOH solution to pH 4-5, and extracted with ethyl acetate (3×150 mL).The combined, cloudy organic solution was concentrated under vacuum todryness. To the residue was added hexane (100 mL), and the mixture wasstirred at room temperature for 1 hr. The clear solution was decantedand the residue was repeated with this operation for two more times. Thesolid material was collected by suction filtration to give a crudeproduct (1.98 g, 5.46 mmol, >100% yield) as a beige solid.

4.1-(4-Chloro-1-(2-methyl-3-nitrophenyl)-5H-pyridazino[4,5-b]indol-7-yl)ethanone

To7-acetyl-1-(2-methyl-3-nitrophenyl)-3H-pyridazino[4,5-b]indol-4(5H)-one(1.88 g, 91.7% pure, 4.75 mmol) at room temperature was added phosphoryltrichloride (350 mL, 3755 mmol), and the mixture was heated at 110° C.for 1 hr. The excess of phosphoryl trichloride was removed under vacuum.The residue was dissolved in ice cold ethyl acetate (900 mL), washedwith water (100 mL), saturated NaHCO₃ solution (2×100 mL), water (100mL), and brine (100 mL). The organic solution was dried over anhydrousMgSO₄ and concentrated under vacuum to dryness to provide the desiredproduct (1.57 g, 4.12 mmol, 86% yield over 2 steps) as a beige solid.

5. Methyl7-acetyl-1-(3-amino-2-methylphenyl)-5H-pyridazino[4,5-b]indole-4-carboxylate

1-(4-Chloro-1-(2-methyl-3-nitrophenyl)-5H-pyridazino[4,5-b]indol-7-yl)ethanone(0.90 g, 2.364 mmol), methanol (30 mL, 740 mmol), DPPF (0.197 g, 0.355mmol), palladium (II) acetate (0.080 g, 0.355 mmol), and sodium acetate(0.388 g, 4.73 mmol) were placed into a steel bomb. The bomb wasevacuated and refilled with nitrogen. This operation was once repeated.The bomb was vacuumed again and then charged with CO (g) at 50 psi. Thebomb was then heated at 95° C. for 20 hr. Upon cooling to roomtemperature, the bomb was further cooled at −78° C. and the excess CO(g) was released. The reaction mixture was diluted with ethyl acetate(20 mL) and filtered through CELITE®. The filtrate was concentratedunder vacuum. The residue was diluted with ethyl acetate (180 mL),washed with water (2×40 mL) and brine (40 mL), and dried over anhydrous.The desired product, methyl7-acetyl-1-(3-amino-2-methylphenyl)-5H-pyridazino[4,5-b]indole-4-carboxylate(0.539 g, 1.440 mmol, 60.9% yield), was isolated as a beige solid byISCO (120 g silica gel, 1-5% methanol/CH₂Cl₂).

6.7-Acetyl-1-(3-amino-2-methylphenyl)-5H-pyridazino[4,5-b]indole-4-carboxamide

A mixture of methyl7-acetyl-1-(3-amino-2-methylphenyl)-5H-pyridazino[4,5-b]indole-4-carboxylate(0.520 g, 1.389 mmol) and ammonia in methanol (30 ml, 210 mmol) washeated in a sealed bottle at 100° C. for 2 hr. Removal of the volatilesunder vacuum gave a crude product (0.501 g) as a tan solid. This crudewas 82% pure, but was used in the next step without furtherpurification.

7. 2-(3-(7-Acetyl-4-carbamoyl-5H-pyridazino[4,5-b]indol-1-yl)-2-methylphenylcarbamoyl)-4-methoxybenzoic acid

A mixture of7-acetyl-1-(3-amino-2-methylphenyl)-5H-pyridazino[4,5-b]indole-4-carboxamide(0.250 g, crude product from the previous step),2-formyl-5-methoxybenzoic acid (0.251 g, 1.391 mmol), sodiumtriacetoxyborohydride (0.442 g, 2.087 mmol), and acetic acid (0.100 mL,1.739 mmol) in dichloromethane (18 mL) and tetrahydrofuran (18 mL) wasstirred at room temperature for 3 hr. Additional sodiumtriacetoxyborohydride (0.442 g, 2.087 mmol) was added and the reactionmixture was stirred at rt. Three hours later, another portion of sodiumtriacetoxyborohydride (0.442 g, 2.087 mmol) was added, and the mixturewas stirred at room temperature overnight. The reaction was quenchedwith water (30 mL) and the mixture was extracted with ethyl acetate(4×40 mL). The combined extract was dried over anhydrous MgSO₄. Removalof solvent under vacuum provided the crude desired product (0.336 g) asa beige solid.

8.7-Acetyl-1-(3-(6-methoxy-1-oxoisoindolin-2-yl)-2-methylphenyl)-5H-pyridazino[4,5-b]indole-4-carboxamide

A mixture of2-((3-(7-acetyl-4-carbamoyl-5H-pyridazino[4,5-b]indol-1-yl)-2-methylphenylamino)methyl)-5-methoxybenzoicacid (0.336 g, the crude product from previous step), BOP (0.852 g,1.925 mmol), and N-methylmorpholine (0.635 mL, 5.78 mmol) in DMF (4 mL)was stirred at 45° C. for 1 hr. The mixture was diluted with ethylacetate (100 mL), washed with water (2×25 mL) and brine (25 mL), anddried over anhydrous MgSO₄. After solvent was removed under vacuum, theresidue were divided into 4 portions and purified by reverse phase HPLC.The correct fractions were combined and concentrated under vacuum,basified with saturated NaHCO₃ solution, and extracted with ethylacetate (3×35 mL). The combined extract was washed with brine (30 mL)and dried over anhydrous MgSO₄. Removal of solvent under vacuum providedthe desired product (40 mg, 0.077 mmol, 11% yield over 3 steps) as ayellow solid. LCMS (M+H)⁺=506.29. ¹H NMR (500 MHz, DMSO-d₆) δ: 12.67 (s,1H), 8.83 (s, 1H), 8.52 (s, 1H), 8.09 (s, 1H), 7.83 (dd, J1=8.5 Hz,J2=1.5 Hz, 1H), 7.77 (dd, J1=7.8 Hz, J2=1.1 Hz, 1H), 7.63-7.60 (m, 2H),7.55 (d, J=6.4 Hz, 1H), 7.47 (d, J=8.3 Hz, 1H), 7.33 (d, J=2.5 Hz, 1H),7.27 (dd, J1=8.3 Hz, J2=2.5 Hz, 1H), 5.02 (d, J=17.2 Hz, 1H), 4.91 (d,J=17.2 Hz, 1H), 3.86 (s, 3H), 2.68 (s, 3H), 1.89 (s, 3H).

EXAMPLE 367-(2-Hydroxypropan-2-yl)-1-(3-(6-methoxy-1-oxoisoindolin-2-yl)-2-methylphenyl)-5H-pyridazino[4,5-b]indole-4-carboxamide

To a solution of7-acetyl-1-(3-(6-methoxy-1-oxoisoindolin-2-yl)-2-methylphenyl)-5H-pyridazino[4,5-b]indole-4-carboxamide(36.0 mg, 0.071 mmol) in tetrahydrofuran (8 mL) at 0° C. was addedmethylmagnesium bromide (0.119 mL, 0.356 mmol). The mixture was stirredat room temperature for 20 min. Additional methylmagnesium bromide(0.119 mL, 0.356 mmol) was added at 0° C. and the mixture was stirred atroom temperature for another 20 min. The reaction was quenched withwater (15 mL). The resulting mixture was extracted with ethyl acetate(3×30 mL). The combined extract was washed with brine (25 mL) and driedover anhydrous MgSO₄. After solvent was removed under vacuum, theresidue was purified by reverse phase HPLC. The correct fraction wasconcentrated under vacuum, basified with saturated NaHCO₃ solution, andextracted with ethyl acetate (3×35 mL). The combined extract was washedwith brine (30 mL) and dried over anhydrous MgSO₄. Removal of solventunder vacuum provided the desired product (11.4 mg, 0.021 mmol, 30.1%yield) as a white solid. LCMS (M+H)⁺=522.20. ¹H NMR (500 MHz, DMSO-d₆)δ: 12.34 (s, 1H), 8.75 (s, 1H), 8.07 (s, 1H), 8.00 (s, 1H), 7.73 (d,J=6.9 Hz, 1H), 7.61-7.57 (m, 2H), 7.51 (d, J=6.4 Hz, 1H), 7.35-7.33 (m,2H), 7.27-7.25 (m, 2H), 5.19 (s, 1H), 4.98 (d, J=16.9 Hz, 1H), 4.90 (d,J=16.9 Hz, 1H), 3.86 (s, 3H), 1.90 (s, 3H), 1.49 (s, 6H).

EXAMPLE 377-(2-Methoxyethoxy)-3-methyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide

1. (E)-Benzyl 2-methyl-3-(2-nitroprop-1-enyl)phenylcarbamate

A solution of benzyl 3-formyl-2-methylphenylcarbamate (5.1667 g, 19.19mmol), nitroethane (6.89 ml, 96 mmol) and ammonium acetate (7.39 g, 96mmol) in acetic acid (Volume: 64.0 ml) under nitrogen was heated at 95°C. After 3 h, the reaction was cooled to room temperature andconcentrated in vacuo. The residue was dissolved in water (40 mL) andCH₂Cl₂ (75 mL), and basified with Na₂CO₃ (s). The layers were separated,and the aqueous layer was extracted with CH₂Cl₂ (2×75 mL). The organiclayers were combined, dried over MgSO₄, filtered and concentrated invacuo. The residue was purified by flash chromatography using an ISCO330 g column eluting with 50-100% hexane/CH₂Cl₂. Appropriate fractionswere collected and concentrated in vacuo to give (E)-benzyl2-methyl-3-(2-nitroprop-1-enyl)phenylcarbamate (2.4714 g, 39.5% yield)as a yellow solid, LC/MS (M+H)=327.16. 0.6875 g of desired product (75%pure by HPLC) was also collected.

2. Benzyl3-(1-(6-(2-methoxyethoxy)-1H-indol-3-yl)-2-nitropropyl)-2-methylphenylcarbamate

(E)-Benzyl 2-methyl-3-(2-nitroprop-1-enyl)phenylcarbamate (0.6849 g,1.574 mmol) and 6-(2-methoxyethoxy)-1H-indole (0.602 g, 3.15 mmol) weredissolved in THF (50 mL), concentrated in vacuo, and melted at 140° C.for 12 h. After cooling to room temperature, the crude product waspurified by flash chromatography using an ISCO 40 g column (solidloading) eluting with 20-75% EtOAc/hexane. Appropriate fractions werecollected and concentrated in vacuo to give benzyl3-(1-(6-(2-methoxyethoxy)-1H-indol-3-yl)-2-nitropropyl)-2-methylphenylcarbamate(0.4102 g, 0.793 mmol, 50.4% yield, mixture of 2 isomers) as a yellowoil, LC/MS (M+H)=518.12, 518.13.

3. Benzyl3-(2-amino-1-(6-(2-methoxyethoxy)-1H-indol-3-yl)propyl)-2-methylphenylcarbamate

A solution of benzyl3-(1-(6-(2-methoxyethoxy)-1H-indol-3-yl)-2-nitropropyl)-2-methylphenylcarbamate(1.6194 g, 3.13 mmol), ammonium acetate (2.51 g, 46.9 mmol) and zinc(3.07 g, 46.9 mmol) in methanol (Ratio: 1.000, Volume: 57.9 ml) andtetrahydrofuran (Ratio: 1.000, Volume: 57.9 ml) was stirred undernitrogen. After 5 h, the reaction was diluted with EtOAc and filteredthrough a wad of CELITE®. The filtrate was concentrated in vacuo, andthe residue was dissolved in EtOAc (75 mL) and saturated aqueous NaHCO₃(30 mL). The layers were separated, and the aqueous layer was extractedwith EtOAc (2×75 mL). The organic layers were combined, dried overMgSO₄, filtered and concentrated in vacuo to give benzyl3-(2-amino-1-(6-(2-methoxyethoxy)-1H-indol-3-yl)propyl)-2-methylphenylcarbamate(1.3975 g, 2.87 mmol, 92% yield, mixture of 2 isomers) as a colorlessoil, LC/MS (M+H)=488.30, 488.30.

4. Ethyl4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-7-(2-methoxyethoxy)-3-methyl-9H-pyrido[3,4-b]indole-1-carboxylate

To a homogeneous, colorless solution of benzyl3-(2-amino-1-(6-(2-methoxyethoxy)-1H-indol-3-yl)propyl)-2-methylphenylcarbamate(1.3975 g, 2.87 mmol) in dioxane (Volume: 143 ml) under nitrogen wereadded 50% ethyl 2-oxoacetate/toluene (1.136 ml, 5.73 mmol) and 4 Nhydrochloric acid/1,4-dioxane (1.433 ml, 5.73 mmol). After stirringovernight, the reaction was concentrated in vacuo, dissolved in EtOAc(75 mL) and saturated aqueous NaHCO₃ (30 mL). The layers were separated,and the aqueous layer was extracted with EtOAc (2×75 mL). the organiclayers were combined, dried over MgSO₄, filtered and concentrated invacuo to give crude cyclized product as a burgundy oil which was used inthe next step. p-Xylene (Volume: 82 ml) and 10% palladium on carbon(0.916 g, 0.861 mmol) were added, and the reaction was heated at 120° C.After 3 h, the reaction was cooled to room temperature, diluted withEtOAc (200 mL) and filtered through a wad of CELITE®. The filtrate wasconcentrated in vacuo, dissolved in EtOAc (125 mL) and washed with water(25 mL). The layers were separated, and the organic layer was dried overMgSO₄, filtered and concentrated in vacuo. The residue was purified byflash chromatography using an ISCO 80 g column eluting with 20-75%EtOAc/hexane. Appropriate fractions were collected and concentrated invacuo to give ethyl4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-7-(2-methoxyethoxy)-3-methyl-9H-pyrido[3,4-b]indole-1-carboxylate(0.6232 g, 1.098 mmol, 38.3% yield) as a tan solid, LC/MS (M+H)=568.24.

5. Benzyl3-(1-carbamoyl-7-(2-methoxyethoxy)-3-methyl-9H-pyrido[3,4-b]indol-4-yl)-2-methylphenylcarbamate

A solution of4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-7-(2-methoxyethoxy)-3-methyl-9H-pyrido[3,4-b]indole-1-carboxylicacid (0.5025 g, 0.931 mmol), ammonium chloride (0.199 g, 3.73 mmol), BOP(0.535 g, 1.211 mmol), DIPEA (0.781 ml, 4.47 mmol) andN-methylmorpholine (0.399 ml, 3.63 mmol) in DMF (Volume: 4.66 ml) wasstirred under nitrogen for 2.5 h. Water (50 mL) was added, and thesolution was stirred for 1 h. The precipitate was filtered, rinsed withwater and dried over Drierite to give benzyl3-(1-carbamoyl-7-(2-methoxyethoxy)-3-methyl-9H-pyrido[3,4-b]indol-4-yl)-2-methylphenylcarbamate(0.4856 g, 0.902 mmol, 97% yield) as a tan solid, LC/MS (M+H)=539.24.

6.4-(3-Amino-2-methylphenyl)-7-(2-methoxyethoxy)-3-methyl-9H-pyrido[3,4-b]indole-1-carboxamide

A solution of benzyl3-(1-carbamoyl-7-(2-methoxyethoxy)-3-methyl-9H-pyrido[3,4-b]indol-4-yl)-2-methylphenylcarbamate(0.4846 g, 0.900 mmol) and 10% palladium on carbon (0.192 g, 0.180 mmol)in tetrahydrofuran (Ratio: 1.000, Volume: 23.99 ml) and methanol (Ratio:1.5, Volume: 36.0 ml) was hydrogenated. After 1.5 h, the reaction wasflushed with nitrogen, filtered through a wad of CELITE®, and rinsed.The filtrate was concentrated in vacuo, dissolved in EtOAc (100 mL),dried over MgSO₄, filtered and concentrated in vacuo to give4-(3-amino-2-methylphenyl)-7-(2-methoxyethoxy)-3-methyl-9H-pyrido[3,4-b]indole-1-carboxamide(0.3800 g, 0.846 mmol, 94% yield) as a solid, LC/MS (M+H)=405.18.

7.7-(2-Methoxyethoxy)-3-methyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide

A sealed pressure tube containing4-(3-amino-2-methylphenyl)-7-(2-methoxyethoxy)-3-methyl-9H-pyrido[3,4-b]indole-1-carboxamide(0.364 g, 0.9 mmol), 1H-benzo[d][1,3]oxazine-2,4-dione (0.367 g, 2.250mmol), trimethoxymethane (0.887 ml, 8.10 mmol) and lanthanum nitratehexahydrate (0.117 g, 0.270 mmol) in tetrahydrofuran (Volume: 4.50 ml)was heated at 95° C. overnight. The reaction was cooled to roomtemperature, diluted with EtOAc (100 mL) and water (30 mL); theinsolubles were filtered, and the layers were separated. The organiclayer was washed with water (30 mL) and brine (30 mL), dried over MgSO₄,filtered and concentrated in vacuo. The residue was purified by flashchromatography using an ISCO 40 g column eluting with 30-100%EtOAc/hexane (solid loading). Appropriate fractions were collected andconcentrated in vacuo to give impure product It was diluted with MeOH (3mL) and DMSO (0.1 mL) and subjected to autoprep HPLC. The appropriatefractions were collected; NaHCO₃ (solid) was added, and the fractionswere concentrated in vacuo not to dryness. It was extracted with CH₂Cl₂(3×); the organic layers were combined, dried over Na₂SO₄, filtered andconcentrated in vacuo to give7-(2-methoxyethoxy)-3-methyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide(0.0372 g, 0.070 mmol, 7.75% yield) as a light tan solid, LC/MS(M+H)=534.18; ¹H NMR (500 MHz, DMSO-d₆) (recognizable peaks for themajor atropoisomer) δ ppm 11.44 (d, J=5.8 Hz, 1H), 8.46 (s, 1H), 8.24(ddd, J=7.9, 3.3, 1.2 Hz, 1H), 8.12-8.17 (m, 1H), 7.85-7.93 (m 1H), 7.79(dd, J=7.9, 2.6 Hz, 1H), 7.71 (br d, J=2.5 Hz, 1H), 7.51-7.68 (m, 2H),7.46 (br ddd, J=7.1, 5.3, 1.4 Hz, 1H), 7.28 (d, J=2.2 Hz, 1H), 6.83 (d,J=8.9 Hz, 1 H), 6.59-6.70 (m, 2H), 4.10-4.16 (m, 2H), 3.69 (br q, J=4.7Hz, 2H), 3.33 (s, 3H), 2.42 (s, 3H), 1.70 (s, 3H).

EXAMPLE 387-(2-Hydroxypropan-2-yl)-3-methyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide

1. Benzyl (2-methyl-3-(2-nitroprop-1-en-1-yl)phenyl)carbamate

A solution of benzyl (3-formyl-2-methylphenyl)carbamate (8.00 g, 29.7mmol), nitroethane (10.7 ml, 149 mmol), and ammonium acetate (11.5 g,149 mmol) was heated in an oil bath at 95° C. overnight. The reactionmixture was concentrated under reduced pressure, and the residue wasdiluted with a mixture of dichloromethane (150 mL) and water (75 mL) andbasified with solid sodium bicarbonate slowly. The organic layer wascollected, and the aqueous layer was extracted with dichloromethane(2×100 mL). The combined organic layers were dried over anhydrous sodiumsulfate. Concentration under reduced pressure followed by purificationby flash silica gel chromatography using a mixture of ethyl acetate inhexane (20%-35%-50%-65%-75%) afforded benzyl(2-methyl-3-(2-nitroprop-1-en-1-yl)phenyl)carbamate (5.16 g, 15.8 mmol,53% yield) as a pale yellow solid.

2. Benzyl(3-(1-(6-bromo-1H-indol-3-yl)-2-nitropropyl)-2-methylphenyl)carbamate

A mixture of (E)-benzyl(2-methyl-3-(2-nitroprop-1-en-1-yl)phenyl)carbamate (5.16 g, 15.8 mmol)and 6-bromo-1H-indole (6.20 g, 31.6 mmol) was heated neat at 140° C.overnight. The crude reaction mixture was purified by flash silica gelchromatography using a mixture of ethyl acetate in hexane (20%-35%-50%)to give benzyl(3-(1-(6-bromo-1H-indol-3-yl)-2-nitropropyl)-2-methylphenyl)carbamate(2.58 g, 4.94 mmol, 31% yield) as a burgundy oil/solid and as a 1:1mixture of diastereomers.

3. Benzyl(3-(2-amino-1-(6-bromo-1H-indol-3-yl)propyl)-2-methylphenyl)carbamate

A solution of benzyl(3-(1-(6-bromo-1H-indol-3-yl)-2-nitropropyl)-2-methylphenyl)carbamate(4.47 g, 8.56 mmol), ammonium chloride (6.87 g, 128 mmol), and zinc dust(8.40 g, 128 mmol) in methanol (100 mL) and tetrahydrofuran (100 mL) wasstirred overnight under nitrogen. The reaction was diluted with ethylacetate and filtered through a pad of CELITE®. The filtrate wasconcentrated under reduced pressure, and the residue was diluted withethyl acetate (150 mL), washed with saturated aqueous sodium bicarbonate(70 mL), and washed with brine (70 mL). The organic layer was collected,and the aqueous layers were sequentially extracted with ethyl acetate(2×100 mL). The combined organic layers were dried over anhydrous sodiumsulfate and concentrated under reduced pressure to give benzyl(3-(2-amino-1-(6-bromo-1H-indol-3-yl)propyl)-2-methylphenyl)carbamate(4.00 g, 8.12 mmol, 95% yield) as a light brown semi-solid and as a ˜1:1diastereomers. LC/MS M+1=492.1 and 494.1.

4. Ethyl4-(3-(((benzyloxy)carbonyl)amino)-2-methylphenyl)-7-bromo-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-carboxylate

To a homogeneous solution of benzyl(3-(2-amino-1-(6-bromo-1H-indol-3-yl)propyl)-2-methylphenyl)carbamate(4.00 g, 8.12 mmol) in dioxane (200 mL) under nitrogen was added 50%ethyl 2-oxoacetate in toluene (3.22 mL, 16.3 mmol) followed by 4 Mhydrochloric acid in 1,4-dioxane (4.06 mL, 16.3 mmol). The reactionmixture was stirred at room temperature overnight. The reaction mixturewas concentrated under reduced pressure, and the residue was dilutedwith ethyl acetate (150 mL), washed with saturated aqueous sodiumbicarbonate (75 mL), and washed with brine (75 mL). The organic layerwas collected, and the aqueous layers were sequentially extracted withethyl acetate (2×100 mL). The combined organic layers were dried overanhydrous sodium sulfate and concentrated under reduced pressure to giveethyl4-(3-(((benzyloxy)carbonyl)amino)-2-methylphenyl)-7-bromo-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-carboxylatein a quantitative yield as a burgundy solid. The mixture was used in thenext step without any further purification. LC/MS M+1=576.2 and 578.2.

5. Ethyl4-(3-(((benzyloxy)carbonyl)amino)-2-methylphenyl)-7-bromo-3-methyl-9H-pyrido[3,4-b]indole-1-carboxylate

A solution of ethyl4-(3-(((benzyloxy)carbonyl)amino)-2-methylphenyl)-7-bromo-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-carboxylate(4.68 g, 8.12 mmol) and 10% palladium on carbon (2.59 g, 2.44 mmol) inxylene (130 mL) was heated at 120° C. overnight. The reaction mixturewas diluted with ethyl acetate and filtered through a pad of CELITE®.The CELITE® pad was washed well with ethyl acetate, and the filtrate wasconcentrated under reduced pressure. The residue was purified by flashsilica gel chromatography using a mixture of ethyl acetate in hexane(20%-35%-50%) to give ethyl4-(3-(((benzyloxy)carbonyl)amino)-2-methylphenyl)-7-bromo-3-methyl-9H-pyrido[3,4-b]indole-1-carboxylate(1.49 g, 2.60 mmol, 32% yield) as a burgundy solid. LC/MS M+1=572.2 and574.2.

6.4-(3-(((Benzyloxy)carbonyl)amino)-2-methylphenyl)-7-bromo-3-methyl-9H-pyrido[3,4-b]indole-1-carboxylicacid

A mixture of ethyl4-(3-(((benzyloxy)carbonyl)amino)-2-methylphenyl)-7-bromo-3-methyl-9H-pyrido[3,4-b]indole-1-carboxylate(1.36 g, 2.38 mmol) and lithium hydroxide, monohydrate (0.399 g, 9.50mmol) in tetrahydrofuran (30 mL), methanol (10 mL), and water (12 mL)was stirred at room temperature for 4 h. The solvent was removed underreduced pressure, and the residue was suspended in water (˜20 mL) and 1Naqueous hydrochloric acid (9.5 mL). The pH was adjusted to 5 with 1Naqueous sodium hydroxide, and the suspension was stirred for 60 min. Thesolid was collected by vacuum filtration, washed with water, and driedovernight to give4-(3-(((benzyloxy)carbonyl)amino)-2-methylphenyl)-7-bromo-3-methyl-9H-pyrido[3,4-b]indole-1-carboxylicacid (1.10 g, 2.02 mmol, 85% yield) as a yellow solid. LC/MS M+1=544.3and 546.3.

7. Benzyl(3-(7-bromo-1-carbamoyl-3-methyl-9H-pyrido[3,4-b]indol-4-yl)-2-methylphenyl)carbamate

A mixture of4-(3-(((benzyloxy)carbonyl)amino)-2-methylphenyl)-7-bromo-3-methyl-9H-pyrido[3,4-b]indole-1-carboxylicacid (1.10 g, 2.02 mmol), ammonium chloride (0.432 g, 8.08 mmol), BOP(1.16 g, 2.63 mmol), N-methylmorpholine (0.866 mL, 7.88 mmol), anddiisopropylethylamine (1.69 mL, 9.70 mmol) in N,N-dimethylformamide(10.0 mL) was stirred at room temperature for 4 h. The reaction mixturewas added dropwise to rapidly stirring water (100 mL). After stirringfor 60 min., the suspension was filtered under reduced pressure, and thesolid was washed with water and dried well under reduced pressure togive benzyl(3-(7-bromo-1-carbamoyl-3-methyl-9H-pyrido[3,4-b]indol-4-yl)-2-methylphenyl)carbamateas a light brown solid. LC/MS M+1=543.4 and 545.4. The reaction mixturewas used in the next step without any further purification.

8.4-(3-Amino-2-methylphenyl)-7-bromo-3-methyl-9H-pyrido[3,4-b]indole-1-carboxamide

To a solution of benzyl(3-(7-bromo-1-carbamoyl-3-methyl-9H-pyrido[3,4-b]indol-4-yl)-2-methylphenyl)carbamate(1.10 g, 2.02 mmol) in acetonitrile (100 mL) at 0° C. was addediodotrimethylsilane (1.10 mL, 8.10 mmol) dropwise. The mixture wasstirred at room temperature for 1.5 h. After concentration, diethylamine(2 mL) and ethyl acetate (150 mL) were added to the residue. The mixturewas washed with water (2×40 mL), washed with brine (40 mL), and driedover anhydrous sodium sulfate. Concentration under reduced pressurefollowed by purification by flash silica gel chromatography using amixture of ethyl acetate in hexane (20%-35%-50%) afforded4-(3-amino-2-methylphenyl)-7-bromo-3-methyl-9H-pyrido[3,4-b]indole-1-carboxamide(0.411 g, 1.00 mmol, 50% yield) as a tan solid. LC/MS M+1=409.1 and411.1.

9.7-Bromo-3-methyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide

A mixture of4-(3-amino-2-methylphenyl)-7-bromo-3-methyl-9H-pyrido[3,4-b]indole-1-carboxamide(0.042 g, 0.103 mmol), 1H-benzo[d][1,3]oxazine-2,4-dione (0.042 g, 0.257mmol), tris(nitrooxy)lanthanum, 6H₂O (0.013 g, 0.031 mmol), andtrimethoxymethane (0.337 mL, 3.08 mmol) in tetrahydrofuran (0.5 mL) in asealed vial was heated at 90° C. for 12 h. The reaction mixture was thenstirred overnight at room temperature. This reaction was repeated twoadditional times. The combined reaction mixtures were diluted with ethylacetate, washed with water, washed with brine, and dried over anhydroussodium sulfate. Concentration under reduced pressure followed bypurification by flash silica gel chromatography using a mixture of ethylacetate and hexane (20%-35%-50%-65%) afforded7-bromo-3-methyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide(0.101 g, 0.188 mmol, 59% yield) as a tan solid. LC/MS M+1=538.1 and540.1.

10.7-Acetyl-3-methyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide

To a well degassed mixture of7-bromo-3-methyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide(0.101 g, 0.188 mmol) and Bis(triphenylphosphine)palladium(II) chloride(0.018 g, 0.026 mmol) in 1,4-dioxane (2.0 mL) in a sealed tube was addedtributyl(1-ethoxyvinyl)stannane (0.148 mL, 0.450 mmol) followed bytriethylamine (0.052 mL, 0.375 mmol). The resulting mixture wasevacuated and charged with nitrogen (2×), immersed in an oil bath at100° C., and stirred overnight. The mixture was diluted with ethylacetate, filtered through a pad of CELITE®, and concentrated underreduced pressure. The residue was dissolved in tetrahydrofuran (5 mL)and stirred with 1 N aqueous hydrochloric acid (2 mL) for 2 h. Thesolution was concentrated under reduced pressure, and the residue wassuspended in water. The pH was adjusted to ˜6 with 1 N sodiumbicarbonate, and the suspension was extracted with ethyl acetate (3×).The combined organic layers were washed with brine and dried overanhydrous sodium sulfate. Concentration under reduced pressure followedby purification by flash silica gel chromatography using a mixture ofethyl acetate and hexane (50%-62%-75%-88%) afforded7-acetyl-3-methyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide(0.051 g, 0.102 mmol, 54% yield) as a pale yellow solid. LC/MSM+1=502.1.

11.7-(2-Hydroxypropan-2-yl)-3-methyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide

To a solution of7-acetyl-3-methyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide(51 mg, 0.102 mmol) in tetrahydrofuran (10.0 mL) at 0° C. was addedmethylmagnesium bromide (3 M in diethyl ether, 0.169 mL, 0.508 mmol).The mixture was stirred for 30 min. HPLC analysis indicated that therewas still a significant amount of starting material remaining.Additional methylmagnesium bromide (0.10 mL) was added, and the reactionmixture was stirred for an additional 30 min. at 0° C. The reaction wasslowly quenched with water and extracted with ethyl acetate (3×). Theorganic layers were combined, washed with brine, and dried overanhydrous sodium sulfate. Concentration under reduced pressure followedby purification by flash silica gel chromatography using a mixture ethylacetate and hexane (50%-62%-75%-88%-100%) and reverse phase preparativeHPLC afforded7-(2-hydroxypropan-2-yl)-3-methyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide(24% yield) as an off-white solid and as a mixture of atropisomers.LC/MS M+1=518.2. ¹H NMR (500 MHz, MeOD) δ 8.42-8.38 (m, 1H), 8.33 (dt,J=8.0, 1.7 Hz, 1H), 7.93-7.87 (m, 1H), 7.83-7.77 (m, 2H), 7.70-7.59 (m,3H), 7.53-7.44 (m, 1H), 7.25-7.15 (m, 1H), 7.06 (d, J=8.6 Hz, 0.6H),6.81 (d, J=8.3 Hz, 0.4H), 2.51-2.46 (m, 3H), 1.81-1.78 (m, 3H), and1.62-1.56 (m, 6H).

EXAMPLE 397-(2-Hydroxypropan-2-yl)-1-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-5H-pyrido[4,3-b]indole-4-carboxamide

1. 7-Bromo-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one

(3-Bromophenyl)hydrazine HCl (20.5730 g, 92.4 mmol) was dissolved in6.25 N aqueous NaOH (16 mL, 100 mmol), ethanol (80 mL) and water (60mL), and extracted with EtOAc (200 mL). The organic layer was dried overMgSO₄, filtered and concentrated in vacuo. CH₂Cl₂ (150 mL) was added,dried over MgSO₄, filtered and concentrated in vacuo to give(3-bromophenyl)hydrazine as a light orange oil. To a heterogeneoussolution of (3-bromophenyl)hydrazine (17.19 g, 92 mmol) in Phenyl ether(82 mL) was added pyridine-2,4-diol (5.11 g, 46.0 mmol). A Dean-Starktrap was set up, and the reaction was heated at 232° C. for 4 hours. Astrong effervescence and gas evolution occurred often for 45 min. Thesolution turned homogeneous with decrease in frequency of strongeffervescence and gas evolution. The reaction mixture was cooled to roomtemperature; precipitation ensued. HPLC and LCMS showed completion ofreaction (86784-071-01). Toluene (100 mL) was added, and the mixturestirred overnight at room temperature. The mixture was filtered and theprecipitate was collected. Methanol (40 mL) was added, and the solutionwas stirred for 20 min. The precipitate was filtered and washed withmethanol, dried to give 7-bromo-2,5-dihydro-1H-pyrido[4,3-b]indol-1-oneas a tan solid. Methanol (60 mL) was added, and the mixture was stirredfor 7 h. The precipitate was collected to give7-bromo-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one (4.4374 g, 16.87 mmol,36.7% yield) a light tan solid. The precipitate was collected to give7-bromo-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one (4.4374 g, 16.87 mmol,36.7% yield) a light tan solid. The product had an HPLC RetentionTime=2.585 min[mixture of rotamers] [4 min grad, 10% MeOH/water to 90%MeOH/water, 0.1% TFA, YMC COMBISCREEN® ODS-A, 4.6×50 mm, 220 nM; LC/MS⁺¹263.04; 265.04

2. Methyl-1-oxo-2,5-dihydro-1H-pyrido[4,3-b]indole-7-carboxylate

A stirred mixture of 7-bromo-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one(1.000 g, 3.80 mmol), 1,1′-Bis(diphenylphosphino)ferrocene (0.319 g,0.57 mmol), Palladium (II) acetate (0.128 g, 0.57 mmol) and Sodiumacetate (0.623 g, 7.600) in a mixture of Methanol (30 mL) and DMA (10mL) was degassed under vacuum and pressurized with Carbon Monoxide gas[CO] from a lecture bottle to approx. 55 psi in a sealed Steel Reactionvessel. The sealed vessel was heated at 95° C. overnight behind aprotective shield. LC-MS showed complete reaction. The reaction mixturewas filtered through a pad of CELITE® and the filtrate concentratedunder vacuum. The residue was diluted with dichloromethane, filtered andthe filtrate concentrated to givemethyl-1-oxo-2,5-dihydro-1H-pyrido[4,3-b]indole-7-carboxylate as a tansolid. [0.732 g product, 3.02 mmol, 85% yield]. The product had an HPLCRetention Time=2.192 min [4 min grad, 10% MeOH/water to 90% MeOH/water,0.1% TFA, YMC COMBISCREEN® ODS-A, 4.6×50 mm, 220 nM]; LC/MS⁺¹ 243.06

3. Methyl-4-bromo-1-oxo-2,5-dihydro-1H-pyrido[4,3-b]indole-7-carboxylate

Bromosuccinimide (0.633 g, 3.56 mmol) was quickly added to a stirredmixture of methyl 1-oxo-2,5-dihydro-1H-pyrido[4,3-b]indole-7-carboxylate(0.783 g, 3.23 mmol) in DMF (20 mL) at room temperature. The reactionwas exothermic and turned brown. The reaction mixture was stirred forfour hours. at room temperature. LC-MS showed complete conversion to thedesired product mass. The reaction mixture was poured in to 200 ml waterwith stirring, then filtered. The residue was washed with water, thenslurred in hot methanol, and filtered. The residue was then dried undervacuum overnight to giveMethyl-4-bromo-1-oxo-2,5-dihydro-1H-pyrido[4,3-b]indole-7-carboxylate asa light brown solid. [0.898 g, 2.80 mmol, 87% yield]. The product had anHPLC Retention Time=2.703 min [4 min grad, 10% MeOH/water to 90%MeOH/water, 0.1% TFA, YMC COMBISCREEN® ODS-A, 4.6×50 mm, 220 nM];LC/MS⁺¹ 320.86, 322.86

4. Methyl-4-cyano-1-oxo-2,5-dihydro-1H-pyrido[4,3-b]indole-7-carboxylate

A stirred mixture of methyl4-bromo-1-oxo-2,5-dihydro-1H-pyrido[4,3-b]indole-7-carboxylate (0.820 g,2.55 mmol) and Cuprous cyanide (0.229 g, 2.55 mmol) inN-Methyl-2-pyrrolidinone (25 mL) was heated at 200° C. for 2-4 hours.LC-MS showed complete conversion to the desired product plus minordebrominated product. The reaction mixture was cooled to roomtemperature then concentrated in vacuo. The residue was slurred in waterand filtered. The solid residue was dried overnight under vacuum to givemethyl-4-cyano-1-oxo-2,5-dihydro-1H-pyrido[4,3-b]indole-7-carboxylate asa brown solid. [0.672 g product, 2.51 mmol, 98% yield]. The product hadan HPLC Retention Time=2.537 min [4 min grad, 10% MeOH/water to 90%MeOH/water, 0.1% TFA, YMC COMBISCREEN® ODS-A, 4.6×50 mm, 220 nM];LC/MS⁺¹ 268.2

5. Methyl-1-chloro-4-cyano-5H-pyrido[4,3-b]indole-7-carboxylate

A stirred slurry of methyl4-cyano-1-oxo-2,5-dihydro-1H-pyrido[4,3-b]indole-7-carboxylate (1.000 g,3.74 mmol) in Dioxane (Volume: 25 mL) was heated to 93° C. Phosphorusoxychloride (1.713 mL, 18.71 mmol) was added slowly dropwise over 30minutes. After complete addition the reaction mixture was stirred at 93°C. for 5 hours then at room temperature overnight. LC-MS showed completeconversion to the desired product mass with minor by-products. Thereaction mixture was diluted with 25 ml ethyl acetate and filtered. Thefiltrate was concentrated under vacuum to give 1.311 g crude solid tanproduct. The crude product was washed with diethyl ether, thentriturated with acetonitrile and filtered to giveMethyl-1-chloro-4-cyano-5H-pyrido[4,3-b]indole-7-carboxylate as a tansolid [0.855 g, 2.99 mmol, 80% yield]. The product had an HPLC RetentionTime=3.658 min [4 min grad, 10% MeOH/water to 90% MeOH/water, 0.1% TFA,YMC COMBISCREEN® ODS-A, 4.6×50 mm, 220 nM]; LC/MS⁺¹ 286.1

6.Methyl-4-cyano-1-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-5H-pyrido[4,3-b]indole-7-carboxylate

A stirred mixture of methyl1-chloro-4-cyano-5H-pyrido[4,3-b]indole-7-carboxylate (0.285 g, 0.998mmol),3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazolin-4(3H)-one(0.361 g, 0.998 mmol), Tetrakis(triphenylphosphine)palladium(0) (0.058g, 0.050 mmol) and Sodium carbonate[2M] (0.499 mL, 0.998 mmol) inDioxane (2 mL) was heated at 110° C. for 16 hours overnight. LC-MSshowed complete conversion to the desired product mass plus residualstarting material[boronic ester] and a byproduct. The reaction mixturewas concentrated. The residue was taken up in 10 ml DMF, stirred andfiltered. The filtrate was concentrated; the residue triturated withmethanol and filtered. The solid residue was dried overnight. LC-MSshowed the solid residue to be the desired productmethyl-4-cyano-1-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-5H-pyrido[4,3-b]indole-7-carboxylateas a tan solid [0.192 g, 0.395 mmol, 39% yield]. The product had an HPLCRetention Time=3.521 min [mixture of rotamers][4 min grad, 10%MeOH/water to 90% MeOH/water, 0.1% TFA, YMC COMBISCREEN® ODS-A, 4.6×50mm, 220 nM]; LC/MS⁺¹ 486.2

7.Methyl-4-carbamoyl-1-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-5H-pyrido[4,3-b]indole-7-carboxylate

A stirred mixture of methyl4-cyano-1-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-5H-pyrido[4,3-b]indole-7-carboxylate(0.192 g, 0.395 mmol) and 90% aqueous Sulfuric acid (2.000 ml, 36.8mmol) was heated at 60° C. for 15-30 minutes. HLC-MS showed completeconversion to the desired product plus the corresponding carboxylicacid. The reaction mixture was cooled to 0° C. and neutralized toapprox. pH=5-6 with 50% NaOH solution then stirred overnight. Thereaction mixture was filtered and the residue dried overnight undervacuum to givemethyl-4-carbamoyl-1-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-5H-pyrido[4,3-b]indole-7-carboxylatea tan/brown solid [0.111 g, 0.220 mmol, 56% yield]. The product had anHPLC Retention Time=2.798 minutes[mixture of isomers] [4 min grad, 10%MeOH/water to 90% MeOH/water, 0.1% TFA, YMC Comb screen ODS-A, 4.6×50mm, 220 nM]; LC/MS⁺¹ 504.4

8.7-(2-Hydroxypropan-2-yl)-1-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-5H-pyrido[4,3-b]indole-4-carboxamide

A solution of methyl4-carbamoyl-1-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-5H-pyrido[4,3-b]indole-7-carboxylate(0.078 g, 0.155 mmol) in THF (20 mL) and HMPA (1.000 mL) was cooled withstirring to −78° C. Methyllithium [1,6M in diethyl ether] (0.620 mL,0.929 mmol) was added quickly drop wise and the resulting reactionmixture stirred at −78° C. for fifteen minutes. The reaction mixture wasallowed to warm to room temperature and quenched with 1N HCl solution [5ml]. The resulting mixture was concentrated under high vacuum. The crudeproduct mixture was chromatographed using Reverse-Phase PREP LC. Thedesired product was obtained as a minor product with two majorby-products. Fractions containing the desired product were combined andconcentrated to give 7.2 mg product plus residual DMF which was pulledoff under high vacuum to give7-(2-hydroxypropan-2-yl)-1-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-5H-pyrido[4,3-b]indole-4-carboxamideas a tan solid product. [0.0055 g, 0.011 mmol, 7.3% yield] The producthad an HPLC Retention Time=3.461 min[mixture of rotamers] [4 min grad,10% MeOH/water to 90% MeOH/water, 0.1% TFA, YMC COMBISCREEN® ODS-A,4.6×50 mm, 220 nM]; LC/MS⁺¹ 504.3. ¹H NMR (400 MHz, methanol-d₄) δ 7.97(s, 1H), 7.85 (dd, J=7.9, 1.3 Hz, 2H), 7.75 (d, J=7.9 Hz, 1H), 7.72-7.61(m, 1H), 7.58 (d, J=0.9 Hz, 1H), 7.50 (dd, J=8.5, 1.4 Hz, 1H), 7.42 (t,2H), 7.33 (d, J=8.4 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 6.79 (s, 1H), 5.55(s, 1H), 5.26 (s, 1H), 3.90-3.64 (m, —OH), 2.25 (s, 3H), 2.10 (s, 3H),1.40-1.12 (m, 6H).

EXAMPLE 401-(3-(8-Fluoro-4-oxoquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-5H-pyrido[4,3-b]indole-4-carboxamide

1.Methyl-4-cyano-1-(3-(8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-methylphenyl)-5H-pyrido[4,3-b]indole-7-carboxylate

A stirred mixture of methyl1-chloro-4-cyano-5H-pyrido[4,3-b]indole-7-carboxylate (0.285 g, 0.998mmol),8-fluoro-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazolin-4(3H)-one(0.379 g, 0.998 mmol), Tetrakis(triphenylphosphine)palladium(0) (0.058g, 0.050 mmol) and Sodium carbonate[2M aqueous] (0.499 mL, 0.998 mmol)in Dioxane (2 mL) was heated at 110° C. for 16 hours overnight. LC-MSshowed complete conversion to the desired product mass plus residualstarting material[boronic ester] and a byproduct. The reaction mixturewas concentrated. The residue was taken up in 10 ml DMF, stirred andfiltered. The filtrate was concentrated; the residue triturated withmethanol and filtered. The solid residue labeled 89040-079-04 was driedovernight. LC-MS showed the solid residue to be the desired productMethyl-4-cyano-1-(3-(8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-methylphenyl)-5H-pyrido[4,3-b]indole-7-carboxylateas a tan solid [0.172 g, 0.342 mmol, 34% yield]. The product had an HPLCRetention Time=3.510 min [mixture of rotamers][4 min grad, 10%MeOH/water to 90% MeOH/water, 0.1% TFA, YMC COMBISCREEN® ODS-A, 4.6×50mm, 220 nM]; LC/MS⁺¹ 504.3.

2.Methyl-4-carbamoyl-1-(3-(8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-methylphenyl)-5H-pyrido[4,3-b]indole-7-carboxylate

A stirred mixture of methyl4-cyano-1-(3-(8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-methylphenyl)-5H-pyrido[4,3-b]indole-7-carboxylate(0.172 g, 0.342 mmol) and 90% aqueous Sulfuric acid (2.000 ml, 36.8mmol) was heated at 60° C. for 15-30 minutes. LC-MS showed completeconversion to the desired product plus the corresponding carboxylic acidas a minor product. The reaction mixture was cooled to 0° C. andcarefully neutralized to approx. pH=5-6 with 50% NaOH solution thenstirred overnight. The reaction mixture was filtered and the residuedried under vacuum overnight to givemethyl-4-carbamoyl-1-(3-(8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-methylphenyl)-5H-pyrido[4,3-b]indole-7-carboxylateas a tan solid. [0.143 g, 0.274 mmol, 80% yield] The product had an HPLCRetention Time=2.798 minutes[mixture of isomers] [4 min grad, 10%MeOH/water to 90% MeOH/water, 0.1% TFA, YMC COMBISCREEN® ODS-A, 4.6×50mm, 220 nM]; LC/MS⁺¹ 522.4.

3.1-(3-(8-Fluoro-4-oxoquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-5H-pyrido[4,3-b]indole-4-carboxamide

In order to overcome the general insolubility of the substrate, asolution of methyl4-carbamoyl-1-(3-(8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-methylphenyl)-5H-pyrido[4,3-b]indole-7-carboxylate(0.100 g, 0.192 mmol) in 0.5 ml DMF concentrated on the rotaryevaporator to product a more amorphous solid. This “amorphous paste” wasdissolved in THF (5 mL) and HMPA (0.500 mL), then cooled with stirringto −78° C. Methyllithium[1.6 M in diethyl ether] (0.615 mL, 0.983 mmol)was added quickly drop wise. An exothermic reaction took place. Theresulting reaction mixture stirred at −78° C. for 15 minutes, thenallowed to warm to 0° C. and quenched with 1N HCl solution andconcentrated under vacuum. The residue was chromatographed usingReverse-Phase PREP LC. to give1-(3-(8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-5H-pyrido[4,3-b]indole-4-carboxamideas a tan solid product. [0.0083 g, 0.015 mmol, 8% yield]. The producthad an HPLC Retention Time=2.623 min[mixture of rotamers] [4 min grad,10% MeOH/water to 90% MeOH/water, 0.1% TFA, YMC COMBISCREEN® ODS-A,4.6×50 mm, 220 nM; LC/MS⁺¹ 522.1. ¹H NMR (400 MHz, methanol-d₄) δ 9.11(s, 1H), 8.07 (br. s., 1H), 7.93-7.87 (m, 2H), 7.86-7.64, 2H), 7.64-7.44(m, 2H), 7.38-7.03 (m, 2H), 6.97-6.39 (m, 1H), 2.26-1.96 (m, 3H),1.77-1.53 (m, 6H).

EXAMPLE 411-(3-(6-Fluoro-1-oxoisoindolin-2-yl)-2-methylphentl)-7-(2-hydroxypropan-2-yl)-5H-pyrido[4,3-b]indole-4-carboxamide

1.Methyl-4-cyano-1-(3-(6-fluoro-1-oxoisoindolin-2-yl)-2-methylphenyl)-5H-pyrido[4,3-b]indole-7-carboxylate

A stirred mixture of methyl1-chloro-4-cyano-5H-pyrido[4,3-b]indole-7-carboxylate (0.285 g, 0.998mmol), Tetrakis(triphenylphosphine)palladium(0) (0.058 g, 0.050 mmol)and Sodium carbonate[2M] (0.499 mL, 0.998 mmol) in Dioxane (10 mL) washeated at 110° C. for 4 hours. LC-MS showed complete conversion to thedesired product mass plus residual starting material[boronic ester] anda byproduct. The reaction mixture was concentrated. The residue wastaken up in 10 ml DMF, stirred and filtered. The filtrate wasconcentrated; the residue triturated with methanol and filtered. Thesolid residue labeled 89040-080-04 was dried overnight to givemethyl-4-cyano-1-(3-(6-fluoro-1-oxoisoindolin-2-yl)-2-methylphenyl)-5H-pyrido[4,3-b]indole-7-carboxylateas a tan solid. [0.216 g, 0.440 mmol, 44% yield]. The product had anHPLC Retention Time=3.498, 3.3.590 min [mixture of rotamers] [4 mingrad, 10% MeOH/water to 90% MeOH/water, 0.1% TFA, YMC COMBISCREEN®ODS-A, 4.6×50 mm, 220 nM]; LC/MS⁺¹ 491.2.

2.Methyl-4-carbamoyl-1-(3-(6-fluoro-1-oxoisoindolin-2-yl)-2-methylphenyl)-5H-pyrido[4,3-b]indole-7-carboxylate

A stirred mixture of [Reactants] and 90% aqueous Sulfuric acid (1.000ml, 18.39 mmol) was heated at 60° C. for 15-30 minutes. LC-MS showedcomplete conversion to the desired product plus the correspondingcarboxylic acid as a minor product. The reaction mixture was neutralizedto approx. pH=5-6 with 50% NaOH solution then stirred overnight. Thereaction mixture was filtered, and the residue dried under vacuumovernight to givemethyl-4-carbamoyl-1-(3-(6-fluoro-1-oxoisoindolin-2-yl)-2-methylphenyl)-5H-pyrido[4,3-b]indole-7-carboxylateas a brown solid. [0.223 g, 0.439 mmol, 96% yield]. The product had anHPLC Retention Time=2.746 min[mixture of isomers] [4 min grad, 10%MeOH/water to 90% MeOH/water, 0.1% TFA, YMC COMBISCREEN® ODS-A, 4.6×50mm, 220 nM]; LC/MS⁺¹ 508.4.

3.1-(3-(6-Fluoro-1-oxoisoindolin-2-yl)-2-methylphentl)-7-(2-hydroxypropan-2-yl)-5H-pyrido[4,3-b]indole-4-carboxamide

In order to overcome the general insolubility of the substrate, asolution of methyl4-carbamoyl-1-(3-(6-fluoro-1-oxoisoindolin-2-yl)-2-methylphenyl)-5H-pyrido[4,3-b]indole-7-carboxylate(0.100 g, 0.197 mmol) in 0.5 ml DMF concentrated on the rotaryevaporator to product a more amorphous solid. This “amorphous paste” wasdissolved in THF (5 mL) and HMPA (0.500 mL) then cooled with stirring to0° C. Methyllithium [1,6M in diethyl ether](0.615 mL, 0.983 mmol) wasadded quickly drop wise. An exothermic reaction took place. Theresulting reaction mixture stirred at 0° C. for 15 minutes then quenchedwith 1N HCl solution. LC-MS showed disappearance of starting material.The reaction mixture was concentrated under vacuum and the residuechromatographed using Reverse-Phase PREP LC. Fractions containingproduct were combined and concentrated to give1-(3-(6-fluoro-1-oxoisoindolin-2-yl)-2-methylphentl)-7-(2-hydroxypropan-2-yl)-5H-pyrido[4,3-b]indole-4-carboxamideas a tan solid [0.0016 g, 0.031 mmol, 16% yield]. The product had anHPLC Retention Time=2.403-2.48 min[mixture of rotamers] [4 min grad, 10%MeOH/water to 90% MeOH/water, 0.1% TFA, YMC COMBISCREEN® ODS-A, 4.6×50mm, 220 nM; LC/MS⁺¹ 509.07. ¹H NMR (400 MHz, methanol-d₄) δ 9.09 (s,1H), 8.07 (br. s., 1H), 7.94-7.86, (m, 2H), 7.84-7.66 (m, 2H), 7.65-7.46(m, 2H), 7.40-7.05 (m, 2H), 4.86 (s, 2H), 2.04 (bs, 4H), 1.63 (bs, 6H).

EXAMPLE 429-(2-Methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-6-carboxamide

1. Ethyl6,9-dibromo-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

A solution of (2,5-dibromophenyl)hydrazine (prepared according to theprocedure of Benniston, A. C. et al., J. Org. Chem., 72:888-897 (2007),5.00 g, 18.80 mmol) in ethanol (150 mL) was treated with ethyl4-oxopiperidine-1-carboxylate (3.22 g, 18.80 mmol) and hydrogenchloride, 4 M in dioxane (4.70 mL, 18.80 mmol). The resulting brownsolution was heated at 80-85° C. on an oil bath for 119.5 h. Afterstirring overnight at room temperature, the solution was concentratedunder vacuum. The residue was sonicated in ethyl acetate and theinsoluble material was collected by filtration, rinsed with EtOAc anddried under vacuum to provide a reddish-brown solid (2.58 g). Thefiltrate was concentrated under vacuum to provide a dark red semisolid(6.23 g) which was sonicated and triturated in a small amount (10-20 mL)of EtOAc. The resulting solid was collected by filtration, rinsed with asmall amount of EtOAc and dried to provide a pink solid (1.473 g). Bothbatches of solid were combined and sonicated in water (with a smallamount of methanol to promote wetting of the solid). The solid wascollected by filtration, rinsed with water and dried under vacuum toprovide a pinkish-tan solid (3.262 g). The original EtOAc filtrate wassubjected to column chromatography on silica gel (220 g), eluting withEtOAc-hexane (gradient from 15:85 to 80:20). The isolated material wasslurred in hexane with a small amount of ethyl acetate, and theprecipitate was collected by filtration and dried under vacuum toprovide a light tan solid (802 mg). The solids were combined to providethe desired product (4.064 g (51%). LCMS (M+H⁺) m/z 401, 403, 405.

2. 6,9-Dibromo-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole

A suspension of ethyl6,9-dibromo-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (2.70g, 6.72 mmol) in ethanol (25 mL) was treated with a solution ofpotassium hydroxide (15.07 g, 269 mmol) in water (15 mL) and ethanol (50mL). The dark brown mixture was bubbled with nitrogen with sonicationfor 1 min. The mixture was then heated under nitrogen to 90-100° C. for44 h, then at reflux for 23 h more. The solution was cooled to roomtemperature and concentrated under vacuum. The residual aqueous sludgewas diluted with water (about 100 mL), stirred and intermittentlysonicated for 1 h, and the precipitate was collected by filtration,washed thoroughly with water and dried under vacuum to provide thedesired product as a light reddish-brown powder (2.123 g, 96% yield).LCMS (M+H⁺) m/z 329, 331, 333).

3. 6,9-Dibromo-2-trityl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole

A suspension of 6,9-dibromo-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(700 mg, 2.121 mmol) in dichloromethane (10 mL) was stirred on anice-water bath and treated with TEA (0.591 mL, 4.24 mmol), DMAP (25.9mg, 0.212 mmol) and trityl chloride (1.183 g, 4.24 mmol). The mixturewas allowed to warmed to room temperature and stirred for 71 h. Thesolution was concentrated under vacuum and the residue was subjected tocolumn chromatography on silica gel (120 g), eluting with EtOAc-hexane(gradient from 5:95 to 50:50) to provide the desired product as a yellowglassy foam (1.388 g) contaminated with a trityl derivative (probablytrityl chloride or triphenylmethanol), estimated purity 75% (estimatedyield of desired product 82%). This material was used without furtherpurification. LCMS m/z 243.2 (trityl cation), 329, 331, 333(M+H-trityl)⁺.

4.9-Bromo-2-trityl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-6-carboxamide

A solution of6,9-dibromo-2-trityl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (purityabout 75%, 650 mg, 0.852 mmol) in THF (10 mL) was stirred at −78° C. andtreated with tert-butyllithium, 1.7 M in pentane (2.505 mL, 4.26 mmol)over 2-3 min. After stirring for about 5-10 min at −78° C., thered-orange solution was stirred on an ice-water bath for 2 h. Thesolution was then cooled again to −78° C. and treated withtrimethylsilyl isocyanate (0.922 mL, 6.81 mmol). Stirring was continuedwhile allowing the cooling bath to warm slowly to room temperature.After 19 h, the mixture was treated with water (5 mL) and extractedtwice with EtOAc. The combined organic phases were dried andconcentrated. The residue was subjected to column chromatography onsilica gel (80 g), eluting with EtOAc-hexane (gradient from 20:80 to100:0) to provide the desired product as an off-white solid (251 mg, 55%yield). LCMS (M+H-trityl)⁺ m/z 294, 296.

5.9-(2-Methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-2-trityl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-6-carboxamide

A mixture of9-bromo-2-trityl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-6-carboxamide(250 mg, 0.466 mmol),3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazolin-4(3H)-one(186 mg, 0.513 mmol), and 2 M aqueous sodium carbonate (0.699 mL, 1.398mmol) in toluene (4 mL) and ethanol (1 mL) was degassed by bubbling withargon for ca. 5-10 min (1 minute with sonication). The mixture wastreated with tetrakis(triphenylphosphine)palladium (26.9 mg, 0.023 mmol)and heated at 90° C. under argon. After 16 h, the mixture was cooled toroom temperature, diluted with EtOAc and a small amount of water and thelayers were separated. The aqueous phase was extracted with EtOAc andthe combined organic phases were filtered, dried and concentrated. Theresidue was subjected to column chromatography on silica gel (40 g),eluting with EtOAc-hexane (gradient from 15:85 to 100:0) to provide thedesired product as a light yellow glass (243 mg, 70% yield). LCMS(M+H-trityl)⁺ m/z 450.2.

6.9-(2-Methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-6-carboxamide

A suspension of9-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-2-trityl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-6-carboxamide(248.5 mg, 0.359 mmol) in methanol (4 mL) was treated with EtOAc (lessthan 1 mL) to form a clear solution. This was treated with 1 M aqueousHCl (3 mL), forming a cloudy mixture which was stirred at roomtemperature. After 30 min, the mixture was concentrated under vacuum,treated with NaHCO₃ (aq) and EtOAc and stirred at room temperature forabout 1 h. The precipitate was collected by filtration, washed withwater, then with EtOAc, and dried under vacuum to provide the desiredproduct as a white solid (145 mg, 90% yield).

Alternatively, a mixture of9-bromo-2-trityl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-6-carboxamide(78.3 mg, 0.146 mmol),3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazolin-4(3H)-one(52.9 mg, 0.146 mmol), and 2 M aqueous sodium carbonate (0.219 mL, 0.438mmol) in toluene (1.2 mL) and ethanol (0.3 mL) was degassed by bubblingwith argon for ca. 5-10 min (1 minute with sonication). The mixture wastreated with tetrakis(triphenylphosphine)palladium (8.4 mg, 0.007 mmol)and heated at 90° C. under argon. After 15.75 h, the mixture was cooledto room temperature and concentrated under vacuum. The residue wasstirred in methanol, treated with a small amount of TFA and water andthe resulting mixture was sonicated until the gummy insoluble materialwas replaced by a flocculent precipitate. The mixture was filtered andsubjected to purification by preparative HPLC. Fractions containing thedesired product by LCMS were combined, treated with saturated aqueoussodium bicarbonate and concentrated under vacuum to provide an aqueoussuspension. The precipitate was collected by filtration, washed withwater and dried under vacuum to provide the desired product as a whitesolid (37.7 mg, 56% yield). LCMS (M+H⁺) m/z 450.2. ¹H NMR (400 MHz,DMSO-d₆) δ 10.83-10.93 (1 H, m), 8.19-8.41 (2 H, m), 8.03 (1 H, br. s.),7.86-7.97 (1 H, m), 7.79 (1 H, t, J=7.3 Hz), 7.58-7.70 (2 H, m),7.41-7.57 (2 H, m), 7.23-7.41 (2 H, m), 6.74-6.88 (1 H, m), 3.02-3.28 (2H, m), 2.90 (2 H, br. s.), 2.71 (2 H, br. s.), 1.76 (3 H, s).

EXAMPLE 432-Acetyl-9-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-6-carboxamide

A cloudy solution of9-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-6-carboxamide(20 mg, 0.044 mmol) in THF (0.5 mL) was treated with TEA (0.019 mL,0.133 mmol) and stirred on an ice-water bath. The mixture was treatedwith acetic anhydride (nominally 8.40 μl, 0.089 mmol, probably more wasadded) and the resulting clear solution was stirred at room temperaturefor 1.5 h. The mixture was concentrated under vacuum, and the residuewas purified by preparative HPLC. Effluent fractions containing thedesired product were treated with NaHCO₃ (aq) and concentrated undervacuum. The resulting aqueous suspension was filtered and theprecipitate was washed with water and dried under vacuum to provide thedesired product as a white solid (7.0 mg). The filter and aqueous phasewere extracted three times with EtOAc, and the organic extracts weredried and concentrated to provide additional desired product as a whitesolid (1.5 mg) for a total of 8.5 mg (39% yield). LCMS (M+H)⁺ m/z 492.2,(M+Na)⁺514.2. ¹H NMR (400 MHz, methanol-d₄) δ 8.30-8.55 (2 H, m),7.87-7.97 (1 H, m), 7.83 (1 H, t, J=7.9 Hz), 7.70 (1 H, dd, J=7.7, 1.3Hz), 7.61-7.68 (1 H, m), 7.44-7.59 (3 H, m), 6.90-7.05 (1 H, m),3.58-4.61 (4 H, m), 2.86-3.08 (2 H, m), 1.80-2.21 (6 H, multiplesinglets).

EXAMPLE 449-(2-Methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-2-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-6-carboxamide

Using the procedure of Example 43 but substituting methanesulfonylchloride in place of acetic anhydride,9-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-6-carboxamide(20 mg, 0.044 mmol) was converted into the desired product as a whitesolid (8.0 mg, 34% yield). LCMS (M+H)⁺ m/z 528.2, (M+Na)⁺550.2. ¹H NMR(400 MHz, DMSO-d₆) δ 8.40, 8.15 (1 H, 2s), 8.22 (1 H, ddd, J=13.9, 8.1,1.3 Hz), 7.92 (1 H, t, J=7.8 Hz), 7.79 (1 H, dd, J=7.6, 4.5 Hz), 7.73 (1H, t, J=8.3 Hz), 7.54-7.67 (2 H, m), 7.51 (1 H, t, J=7.7 Hz), 7.43 (1 H,dd, J=7.2, 5.6 Hz), 6.83-7.00 (1 H, m), 3.43-3.86 (3 H, m), 3.28-3.34 (3H, m), 2.89-3.19 (3 H, m), 1.74 (3 H, 2s).

EXAMPLE 45 N2,N2-Dimethyl-9-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2,6(5H)-dicarboxamide

Using the procedure of Example 43 but substituting dimethylcarbamoylchloride in place of acetic anhydride,9-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-6-carboxamide(20 mg, 0.044 mmol) was converted into the desired product as a whitesolid (10.0 mg, 42% yield). LCMS (M+H)⁺ m/z 521.3, (M+Na)⁺543.3. ¹H NMR(400 MHz, methanol-d₄) δ 8.29-8.40 (2 H, m), 7.88-7.98 (1 H, m),7.77-7.87 (1 H, m), 7.61-7.72 (2 H, m), 7.45-7.60 (3 H, m), 6.90-7.04 (1H, m), 3.37-4.09 (4 H, m), 2.83-3.08 (2 H, m), 2.65-2.82 (6 H, 2s), 1.87(3 H, 2s).

EXAMPLE 46 Ethyl6-carbamoyl-9-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

Using the procedure of Example 43 but substituting ethyl chloroformatein place of acetic anhydride,9-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-6-carboxamide(20 mg, 0.044 mmol) was converted into the desired product as a whitesolid (14.0 mg, 59% yield). LCMS (M+H)⁺ m/z 522.3. ¹H NMR (400 MHz,methanol-d₄) δ 8.16-8.56 (2 H, m), 7.87-7.98 (1 H, m), 7.76-7.87 (1 H,m), 7.61-7.73 (2 H, m), 7.42-7.59 (3 H, m), 6.89-7.06 (1 H, m),3.42-4.22 (6 H, m), 2.79-3.01 (2 H, m), 1.86 (3 H, br. s.), 1.12-1.36 (3H, m).

EXAMPLE 479-(2-Methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-5H-pyrido[4,3-b]indole-6-carboxamide

A mixture of9-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-6-carboxamide(10 mg, 0.022 mmol) and activated manganese dioxide (19.34 mg, 0.222mmol) in butyl acetate (0.5 mL) was heated on an oil bath at 110° C. for5.25 h, then at 90-100° C. for 2.5 days, then at 125° C. for 20 h. Themixture was cooled to room temperature, diluted with methanol, filteredand concentrated under vacuum. The residue was purified by preparativeHPLC. The effluent containing the desired product was concentrated undervacuum to provide a fine aqueous suspension. This was extracted threetimes with EtOAc, and the combined organic phases were dried andconcentrated to provide the desired product as an off-white solid (3.5mg, 33% yield). LCMS (M+H)+ m/z 446.2. ¹H NMR (400 MHz, methanol-d₄) δ8.31-8.47 (3.6 H, m), 8.06-8.16 (1.4 H, m), 7.87-7.96 (1 H, m),7.76-7.87 (1 H, m), 7.55-7.70 (5 H, m), 7.24-7.36 (1 H, m), 1.90 (3 H,2s).

EXAMPLE 485-(2-Methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-8-carboxamide

1. 4,7-Dibromo-1H-indole

To a solution of 1,4-dibromo-2-nitrobenzene (18 g, 64.1 mmol) in THF(200 mL) at −40° C. (dry ice-acetonitrile) was added slowly a solutionof vinylmagnesium bromide (1.0 M in THF, 199 mL, 199 mmol). Theresulting mixture was stirred at −40° C. for 1.5 h, then was thentreated with saturated aqueous NH₄Cl (500 mL) and stirred at roomtemperature for 1 h. HCl (1M) was added to adjust the pH to 7. EtOAc wasadded and the organic phase was separated, washed with brine, dried andconcentrated. The residue was subjected to column chromatography onsilica gel (330 g), eluting with EtOAc-hexane (5:95) to provide a lightyellow oil which solidified on standing under vacuum. The desiredproduct was obtained as a solid (8.35 g, 47% yield. LCMS showed onemajor peak with no ionization.

2. 4-Bromo-1H-indole-7-carboxylic acid

To a solution of 4,7-dibromo-1H-indole (8.53 g, 31.0 mmol) in THF (124mL) at −78° C. was slowly added n-butyllithium (2.5 M in hexane, 49.6mL, 124 mmol). The solution was stirred at 0-5° C. for 2 h, then wascooled to −78° C. and bubbled with carbon dioxide gas for 15 min. Thereaction mixture was allowed to warm to room temperature for 1 h, thenwas treated with water and partitioned between EtOAc and 1 M aqueousHCl. The organic phase was washed with brine, dried and concentrated toafford the desired product as a light yellow solid (10.04 g) which wasabout 75% pure by LCMS, and was used without further purification. LCMS(M−H)⁻: 238, 240.

3. 4-Bromo-1H-indole-7-carboxamide

A mixture of 4-bromo-1H-indole-7-carboxylic acid (10.04 g, 75% purity,31.2 mmol), EDC (8.96 g, 46.7 mmol), and 1-hydroxybenzotriazole hydrate(7.16 g, 46.7 mmol) in THF (198 mL) and CH₂Cl₂ (247 mL) was stirred atroom temperature for 1 h. The mixture was then bubbled with NH₃ gas for15 min and stirred at room temperature for 4 h. LCMS showed residualstarting material, so aqueous ammonium hydroxide (4.85 mL, 125 mmol) wasadded and the mixture was stirred at room temperature overnight. After20 h, the mixture was concentrated and partitioned between NaHCO₃ (aq)and EtOAc. The organic phase was washed with brine, dried andconcentrated. The residue was suspended in EtOAc and the solid wascollected by filtration and air-dried to provide the desired product.The filtrates were subjected to column chromatography on silica gel (40g), eluting with EtOAc-hexane (gradient from 20:80 to 50:50) to provideadditional desired product for a total of 4.86 g (65% yield) over twosteps. LCMS (M−H)⁻: 237.2, 239.2.

4. 4-Bromo-3-(2-nitrovinyl)-1H-indole-7-carboxamide

A dark red-brown solution of 4-bromo-1H-indole-7-carboxamide (0.79 g,3.30 mmol) and (E)-N,N-dimethyl-2-nitroethenamine (0.422 g, 3.63 mmol)in TFA (9.44 mL) was stirred at room temperature overnight. After 16 h,LCMS indicated residual starting materials in addition to desiredproduct. Additional (E)-N,N-dimethyl-2-nitroethenamine (77 mg) was addedand the mixture was stirred at room temperature for 6 h. The mixture waspartitioned between 1 M NaOH (pH was adjusted to ca. 4) and EtOAc. Theorganic phase was washed with NaHCO₃ (aq) and brine, dried andconcentrated to afford a bright orange-red solid. The crude product wassuspended in EtOAc and the desired product was collected by filtration,washed with EtOAc and air dried to provide a solid (0.89 g, 87% yield).LCMS (M+H)⁺ m/z 309.7, 311.7.

5. 3-(2-Aminoethyl)-4-bromo-1H-indole-7-carboxamide

To a suspension of (Z)-4-bromo-3-(2-nitrovinyl)-1H-indole-7-carboxamide(0.50 g, 1.612 mmol) in THF (53.7 mL) at 0° C. was slowly added asolution of lithium aluminum hydride (1 M in THF, 8.06 mL, 8.06 mmol).The mixture was stirred at room temperature overnight. After 16 h, themixture was treated sequentially with water (0.50 mL), 5 M aqueoussodium hydroxide (0.50 mL), and water (1.5 mL), then was diluted with asolvent mixture of THF, methanol, and EtOAc. The resulting mixture wasfiltered through a CELITE® pad, washed with THF, methanol, and DMSO. Thefiltrates were concentrated and residue was partitioned between EtOAcand NaHCO₃ (aq). The organic phase was washed with brine, dried andconcentrated to afford a brown solution which was subjected topreparative HPLC to provide the desired product as the TFA salt (100 mg,16% yield). LCMS (M+H)⁺ m/z 281.8, 283.8.

6. 5-Bromo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-8-carboxamide

To a solution of 3-(2-aminoethyl)-4-bromo-1H-indole-7-carboxamide, TFAsalt (0.068 g, 0.172 mmol) in methanol (1.2 mL) was added 1 M aqueousHCl (0.933 mL) and 37% aqueous formaldehyde (0.042 mL, 0.515 mmol) andthe resulting solution was heated at 80° C. for 18 h. The mixture wasconcentrated and the residue was purified by preparative HPLC to providethe desired product as the TFA salt (21 mg, 30% yield). LCMS (M+H)⁺ m/z2937,295.7.

7.5-(2-Methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-8-carboxamide

Using the procedure described in step 5 of Example 42 followed bypurification by preparative HPLC, the desired product was obtained from5-bromo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-8-carboxamide as theTFA salt (14.5 mg, 40% yield). LCMS (M+H)⁺ m/z 450.2. ¹H NMR (400 MHz,methanol-d₄) δ 8.38-8.25 (m, 2H), 7.99-7.86 (m, 1H), 7.82 (d, J=8.1 Hz,1H), 7.78-7.73 (m, 1H), 7.68-7.61 (m, 1H), 7.57-7.42 (m, 3H), 7.09-6.96(m, 1H), 4.48 (s, 2H), 3.52-3.34 (m, 2H), 2.77-2.22 (m, 2H), 1.89-1.78(m, 3H).

8.5-(2-Methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-8-carboxamide

Using the procedure described in Example 47 followed by purification bypreparative HPLC, the desired product was obtained as the TFA salt (7mg, 34% yield) from5-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-8-carboxamide.LCMS (M+H)⁺ m/z 446.1. ¹H NMR (400 MHz, DMSO-d₆) δ 12.75 (br. s., 1H),9.26 (s, 1H), 8.60-8.29 (m, 4H), 8.27-8.20 (m, 1H), 7.96-7.88 (m, 1H),7.87-7.71 (m, 3H), 7.65 (dt, J=15.6, 7.5 Hz, 2H), 7.56 (d, J=7.7 Hz,1H), 7.52-7.23 (m, 2H), 1.80-1.69 (m, 3H).

EXAMPLE 493-(Hydroxymethyl)-5-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-8-carboxamide

1. 4-Bromo-3-((dimethylamino)methyl)-1H-indole-7-carboxamide

Acetic acid (1.15 mL, 20.08 mmol) was added to a suspension of4-bromo-1H-indole-7-carboxamide (3 g, 12.55 mmol), paraformaldehyde(0.603 g, 20.08 mmol) and dimethylamine (2 M in methanol, 10 mL, 20.08mmol) in ethanol (50 mL). The mixture was heated to 80° C. After 2 h,the ethanol was removed under vacuum. The residue was partitionedbetween NaHCO₃ (aq) and EtOAc. The organic phase was washed with brine(15 mL), dried and concentrated to afford the crude desired product as alight brown solid (4.08 g). LCMS (M+H)⁺ m/z 295.8, 297.8.

2. Ethyl 3-(4-bromo-7-carbamoyl-1H-indol-3-yl)-2-nitropropanoate

Methyl propiolate (2.300 mL, 27.5 mmol) was added slowly to a suspensionof crude 4-bromo-3-((dimethylamino)methyl)-1H-indole-7-carboxamide (6.27g, 21.17 mmol) and ethyl 2-nitroacetate (3.66 g, 27.5 mmol) indichloromethane (151 mL) and acetonitrile (151 mL). After 30 min, themixture was concentrated and partitioned between EtOAc and 1 M aqueousHCl. The organic phase was washed with NaHCO₃ (aq) and brine, dried andconcentrated. The residue was coated subjected to column chromatographyon silica gel (80 g), eluting with EtOAc-hexane (gradient from 50:50 to80:20) to provide the desired product as a solid (4.60 g, 57% yield).LCMS (M+H)⁺ m/z 383.8, 385.8.

3. Ethyl 2-amino-3-(4-bromo-7-carbamoyl-1H-indol-3-yl)propanoate

A solution of ethyl3-(4-bromo-7-carbamoyl-1H-indol-3-yl)-2-nitropropanoate (4.6 g, 11.97mmol) in isopropanol (200 mL) and THF (100 mL) was cooled in an ice bathand treated portionwise with zinc dust (8.85 g, 135 mmol), followed by 1M aqueous HCl (150 mL) in portions. The mixture was stirred at roomtemperature for 3 h, then treated with NaOH pellets and 1 M aqueous NaOHto pH 9-10. The mixture was diluted with THF and EtOAc, stirred for 15min and filtered through a CELITE® pad. The solids were rinsed withEtOAc, THF, and NaHCO₃ (aq). The filtrates were concentrated to removemost of the organic solvents, and the aqueous residue was extracted withEtOAc. The combined extracts were washed with brine, dried andconcentrated to provide the desired product as an off-white solid (3.65g, 86% yield). LCMS (M+H)⁺ m/z 353.8, 355.8.

4. Ethyl5-bromo-8-carbamoyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate

To a solution of ethyl2-amino-3-(4-bromo-7-carbamoyl-1H-indol-3-yl)propanoate (3.45 g, 9.74mmol) in methanol (68.8 mL) and 1 M aqueous HCl (52.9 mL) was added 37%aqueous formaldehyde (0.790 mL, 9.74 mmol) and the resulting mixture washeated at 80° C. After 1.5 h, additional formaldehyde (0.79 mL) wasadded and heating was continued. After 3.5 h, additional formaldehyde(0.79 mL) was again added and heating was continued. After 6 h, themixture was cooled to room temperature, concentrated, and partitionedbetween a solvent mixture of CHCl₃ and iPrOH (3:1) and 1 M NaOH andNaHCO₃ (aq). The organic phase was washed with brine, dried andconcentrated to afford the crude product as a light brown solid (3.16 g,89% yield). LCMS (M+H)⁺ m/z 365.8, 367.8.

5. Ethyl 5-bromo-8-carbamoyl-9H-pyrido[3,4-b]indole-3-carboxylate

Using the procedure described in Example F, ethyl5-bromo-8-carbamoyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylatewas converted to the desired product as a brown solid (0.71 g, 72%yield). LCMS (M+H)⁺ m/z 361.8, 363.8.

6. 5-Bromo-3-(hydroxymethyl)-9H-pyrido[3,4-b]indole-8-carboxamide

Using the procedure described in step 5 of Example 48, ethyl5-bromo-8-carbamoyl-9H-pyrido[3,4-b]indole-3-carboxylate was convertedto the desired product as a tan solid (102 mg, 36% yield). LCMS (M+H)⁺m/z 319.8, 321.8.

7.3-(Hydroxymethyl)-5-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-8-carboxamide

Using the procedure described in step 5 of Example 2,5-bromo-3-(hydroxymethyl)-9H-pyrido[3,4-b]indole-8-carboxamide wasconverted to the desired product, isolated as the TFA salt (1.8 mg, 4%yield). LCMS (M+H)⁺ m/z 475.9. ¹H NMR (500 MHz, methanol-d₄) δ 9.05 (s,1H), 8.40 (d, J=7.4 Hz, 1H), 8.35-8.29 (m, 2H), 7.93-7.88 (m, 1H), 7.83(d, J=8.4 Hz, 1H), 7.71-7.60 (m, 5H), 7.45 (d, J=7.4 Hz, 1H), 5.26 (d,J=15.4 Hz, 1H), 5.01 (d, J=15.4 Hz, 1H), 1.86-1.83 (m, 3H).

EXAMPLE 503-(2-Hydroxypropan-2-yl)-5-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-8-carboxamide

1. 5-Bromo-3-(2-hydroxypropan-2-yl)-9H-pyrido[3,4-b]indole-8-carboxamide

A solution of ethyl5-bromo-8-carbamoyl-9H-pyrido[3,4-b]indole-3-carboxylate (0.4 g, 1.104mmol) in THF (31.6 mL) was cooled in a salt-ice bath slowly treated withmethylithium (1.6 M in ether, 3.80 mL, 6.07 mmol). The solution wasstirred at −5° C. for 1.5 h, then was treated with ice and 1 M aqueousHCl (7 mL). The mixture was made basic with NaHCO₃ (aq) and extractedwith chloroform-isopropanol (3:1). The organic phase was washed withbrine, dried and concentrated. The residue was subjected to columnchromatography on silica gel (40 g), eluting with Methanol-CH₂Cl₂(gradient from 2:98 to 10:90) to provide the desired product as a yellowsolid (128 mg, 33% yield). LCMS (M+H)⁺ m/z 347.9, 349.9.

2.3-(2-Hydroxypropan-2-yl)-5-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-8-carboxamide

Using the procedure described in step 5 of Example 42,5-bromo-3-(2-hydroxypropan-2-yl)-9H-pyrido[3,4-b]indole-8-carboxamidewas converted to the desired product (14 mg, 33% yield). LCMS (M+H)⁺ m/z503.9. ¹H NMR (500 MHz, methanol-d₄) δ 9.00-8.98 (m, 1H), 8.36 (d, J=7.9Hz, 1H), 8.29-8.22 (m, 2H), 7.90-7.84 (m, 1H), 7.79 (d, J=7.9 Hz, 1H),7.69-7.64 (m, 1H), 7.62-7.60 (m, 2H), 7.53 (d, J=7.4 Hz, 1H), 7.42-7.35(m, 2H), 1.83 (s, 3H), 1.73 (s, 3H), 1.62 (s, 3H).

EXAMPLE 515-(2-Methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-3,8-dicarboxamide

1. Ethyl8-carbamoyl-5-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-3-carboxylate

Using the procedure described in step 5 of Example 42, ethyl5-bromo-8-carbamoyl-9H-pyrido[3,4-b]indole-3-carboxylate was convertedto the desired product (170 mg, 37% yield). LCMS (M+H)⁺ m/z 517.9.

2.8-Carbamoyl-5-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-3-carboxylicacid

A solution of ethyl8-carbamoyl-5-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-3-carboxylate(0.26 g, 0.502 mmol) and lithium hydroxide monohydrate (0.070 g, 1.757mmol) in THF-ethanol-water (3:1:1, 20.10 mL) was stirred at roomtemperature overnight. After 18 h, residual starting material wasobserved by LCMS. The mixture was heated at 50° C. for 2 h, then cooledto room temperature and concentrated. The residue was suspended in waterand treated with 1 M aqueous HCl (to pH 1-2). The precipitate wascollected by filtration, washed with water and dried to provide thedesired product as a pale yellow solid (0.205 g, 76%). LCMS (M+H)⁺ m/z490.1.

3.5-(2-Methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-3,8-dicarboxamide

Using the procedure described in step 3 of Example 48,8-Carbamoyl-5-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-3-carboxylicacid was converted to the desired product (5.3 mg, 18% yield). LCMS(M+H)⁺ m/z 488.9. ¹H NMR (500 MHz, methanol-d₄) δ 9.27-8.91 (m, 1H),8.65-8.14 (m, 3H), 8.03-7.66 (m, 4H), 7.65-7.52 (m, 3H), 7.50-7.30 (m,1H), 1.89 (m, 3H).

EXAMPLE 523-(Hydroxymethyl)-9-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-5H-pyrido[4,3-b]indole-6-carboxamide

1. 4-Bromo-3-formyl-1H-indole-7-carbonitrile

A solution of DMF (8.42 mL, 109 mmol) in CH₂Cl₂(105 mL) stirred on asalt-ice bath was treated dropwise with phosphorus oxychloride (2.57 mL,27.6 mmol). After 15 min, 4-bromo-1H-indole-7-carboxamide (2 g, 8.37mmol) was added in one portion while maintaining the temperature below−10° C. After addition, the mixture was stirred at room temperatureovernight. After 16 h, ice was added, followed by NaHCO₃ and 1 M aqueousNaOH added in portions to make the mixture basic. The mixture wasextracted with dichloromethane (3 times), and the combined organicphases were washed with brine, dried and concentrated. The residue wassubjected to column chromatography on silica gel (80 g), eluting with agradient from 100% CH₂Cl₂ to 15% Methanol-85% CH₂Cl₂, to provide thedesired product as a pale solid (1.36 g, 65% yield). LCMS (M+H)⁺ m/z248.9, 250.9.

2. Ethyl2-((4-bromo-7-cyano-1H-indol-3-yl)methylamino)-3,3-diethoxypropanoate

A mixture of 4-bromo-3-formyl-1H-indole-7-carbonitrile (1.08 g, 4.34mmol), ethyl 2-amino-3,3-diethoxypropanoate (prepared according to theprocedure of U.S. Pat. No. 7,470,680; 1.780 g, 6.94 mmol), and molecularsieves (2.17 g, 2 g) in 1,2-dichloroethane (79 mL) and THF (29.6 mL) at0° C. was treated with sodium triacetoxyborohydride (2.57 g, 12.14 mmol)and the resulting mixture was stirred at room temperature overnight.After 24 h, LCMS residual starting material, so additional sodiumtriacetoxyborohydride (1.38 g, 1.5 eq.) and molecular sieves (2 g) wereadded and stirring was continued for 4 h more. The mixture was dilutedwith EtOAc and filtered through a CELITE® pad and the solids were washedwith EtOAc. The filtrates were diluted with EtOAc and washed with NaHCO₃(aq) and brine, dried and concentrated to afford a dark-colored oil. Theresidue was subjected to column chromatography on silica gel (40 g),eluting with EtOAc-hexane (gradient from 15:85 to 100:0) to provide thedesired product as a brown syrup (0.67 g, 35% yield). LCMS (M+H)⁺ m/z438.2, 440.2.

3. Ethyl 9-bromo-6-cyano-5H-pyrido[4,3-b]indole-3-carboxylate

To a solution of ethyl2-(((4-bromo-7-cyano-1H-indol-3-yl)methyl)amino)-3,3-diethoxypropanoate(1.12 g, 2.56 mmol) in toluene (51.1 mL) at 0° C. was added dropwisetitanium tetrachloride (1 M in CH₂Cl₂, 8.94 mL, 8.94 mmol). The mixturewas heated at 90° C. for 3 h. The mixture was cooled to room temperatureand partitioned between NaHCO₃ (aq) and EtOAc. The organic phase waswashed with brine, dried and concentrated. The resulting dark yellowsolid was suspended in methanol, then collected by filtration andair-dried to afford the desired product as a yellow solid (300 mg, 29%yield), contaminated with partially aromatized material (ethyl9-bromo-6-cyano-4,5-dihydro-3H-pyrido[4,3-b]indole-3-carboxylate and/orethyl 9-bromo-6-cyano-2,5-dihydro-1H-pyrido[4,3-b]indole-3-carboxylate)and ethyl9-bromo-6-cyano-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-3-carboxylate,which was used without further purification. LCMS (M+H)⁺ m/z 343.9,345.9.

4. 9-Bromo-6-carbamoyl-5H-pyrido[4,3-b]indole-3-carboxylic acid

A suspension of crude ethyl9-bromo-6-cyano-5H-pyrido[4,3-b]indole-3-carboxylate (0.78 g, 2.266mmol) and sodium perborate tetrahydrate (1.395 g, 9.07 mmol) inethanol-water (3:2, 99 mL) was heated at 100° C. for 3 h. The mixturewas cooled to room temperature and the ethanol was removed under vacuumto give a suspension. The pH was adjusted to about 5-6 with 1 M aqueousHCl. The precipitate was collected by filtration, washed with water andair-dried to afford the desired product (0.60 g). The filtrate wasconcentrated under vacuum to provide additional desired product (70 mg,total of 88% yield). LCMS (M+H)⁺ m/z 334.0, 335.9.

5. Methyl 9-bromo-6-carbamoyl-5H-pyrido[4,3-b]indole-3-carboxylate

To a mixture of 9-bromo-6-carbamoyl-5H-pyrido[4,3-b]indole-3-carboxylicacid (0.61 g, 1.187 mmol), EDC (0.455 g, 2.373 mmol),1-hydroxybenzotriazole hydrate (0.363 g, 2.373 mmol),4-dimethylaminopyridine (0.145 g, 1.187 mmol), and diisopropylethylamine(0.829 mL, 4.75 mmol) in DMF (79 mL) was added methanol (4.80 mL, 119mmol). The mixture was stirred at room temperature for 20 h, then waspartitioned between EtOAc and NaHCO₃ (aq). The organic phase was washedwith brine, dried and concentrated to afford a yellow oil. This materialwas subjected to preparative HPLC to provide the desired product as theTFA salt (132 mg, 32% yield). LCMS (M+H)⁺ m/z 348.0, 350.0.

6. 9-Bromo-3-(hydroxymethyl)-5H-pyrido[4,3-b]indole-6-carboxamide

Using the procedure described in step 5 of Example 48, methyl9-bromo-6-carbamoyl-5H-pyrido[4,3-b]indole-3-carboxylate was convertedto the desired product, isolated by preparative HPLC as the TFA salt (40mg, 27% yield). LCMS (M+H)⁺ m/z 320.0, 322.0.

7. 3-(3-Bromo-2-methylphenyl)quinazolin-4(3H)-one

A mixture of 1H-benzo[d][1,3]oxazine-2,4-dione (200 mg, 1.226 mmol),3-bromo-2-methylaniline (228 mg, 1.226 mmol), and trimethoxymethane (390mg, 3.68 mmol) in THF (2 mL) was heated overnight in a sealed tube at100° C. The mixture was cooled to room temperature and concentrated, andthe residue was purified by column chromatography, eluting withEtOAc-hexane (gradient from 10:90 to 50:50) to provide the desiredproduct (140 mg, 36% yield). LCMS (M+H)⁺ m/z 315, 317.

8.3-(2-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazolin-4(3H)-one

A mixture of 3-(3-bromo-2-methylphenyl)quinazolin-4(3H)-one (0.89 g,2.82 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(1.076 g, 4.24 mmol), potassium acetate (0.831 g, 8.47 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complexwith CH₂Cl₂ (0.115 g, 0.141 mmol) in dioxane (10 mL) was heated at 110°C. for 5 h. The mixture was cooled to room temperature, diluted withEtOAc and washed with water. The organic phase was filtered, dried andconcentrated. The residue was purified by column chromatography onsilica gel (40 g), eluting with EtOAc-hexane (gradient from 20:80 to40:60) to provide3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazolin-4(3H)-oneas a white glassy foam (800 mg, 78% yield). LCMS (M+H)⁺ m/z 363.2.

9.3-(Hydroxymethyl)-9-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-5H-pyrido[4,3-b]indole-6-carboxamide

Using the procedure described in step 5 of Example 42,9-Bromo-3-(hydroxymethyl)-5H-pyrido[4,3-b]indole-6-carboxamide wasconverted to the desired product (13.7 mg, 31% yield). LCMS (M+H)⁺ m/z476.1. ¹H NMR (500 MHz, DMSO-d₆) δ 11.99 (br. s., 1H), 8.46-8.41 (m,1H), 8.28 (br. s., 1H), 8.26-8.21 (m, 1H), 8.15-7.97 (m, 2H), 7.94-7.88(m, 1H), 7.82-7.75 (m, 2H), 7.71-7.66 (m, 1H), 7.65-7.58 (m, 3H),7.57-7.48 (m, 1H), 7.22-7.13 (m, 1H), 5.44 (br. s., 1H), 4.70-4.58 (m,2H), 1.79 (s, 3H).

Following the procedure for Examples 1-52, additional Examples 53-117listed in Table 3 were prepared.

TABLE 3 Example No. Structure (M + H)⁺ 53

306.15 54

324.14 55

581.24 56

336.10 57

427.18 58

529.14 59

528.15 60

525.20 61

524.21 62

322.06 63

391.13 64

524.21 65

520.12 66

540.17 67

546.26 68

527.30 69

547.26 70

518.23 71

565.27 72

546.29 73

569.28 74

566.35 75

553.38 76

554.36 77

556.31 78

537.36 79

511.23 80

507.30 81

527.09 82

541.32 83

545.25 84

521.34 85

529.25 86

497.19 87

538.16 88

524.17 89

538.22 90

524.19 91

518.22 92

552.26 93

548.32 94

549.27 95

549.26 96

549.28 97

549.28 98

521.21 99

528.22 100

526.16 101

505.28 102

492.18 103

508.15 104

524.16 105

525.18 106

511.15 107

476.14 108

481.0  (M + H)⁺ 109

522.0  (M + H)⁺ 110

522.0  (M + H)⁺ 111

522.0  (M + H)⁺ 112

522.0  (M + H)⁺ 113

509.0  (M + H)⁺ 114

517.1  (M + H)⁺ 115

503.3  (M + H)⁺ 116

559.0  (M + H)⁺ 117

517.2  (M + H)⁺

Intermediates

In addition to the intermediates mentioned in preparation of Examples1-52, additional intermediates shown in Table 4 were synthesized.

Intermediate 16-Fluoro-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazolin-4(3H)-one

1. 3-(3-Bromo-2-methylphenyl)-6-fluoroquinazolin-4(3H)-one

A mixture of 2-amino-5-fluorobenzoic acid (1.00 g, 6.45 mmol),3-bromo-2-methylaniline (1.199 g, 6.45 mmol) and triethoxymethane (0.955g, 6.45 mmol) in THF (2 mL) was heated at 110° C. overnight in a sealedtube. The mixture was cooled to room temperature and diluted with EtOAc.The solution was washed with NaHCO₃ (aq) and water, then was dried andconcentrated. The residue was purified by column chromatography, elutingwith EtOAc-hexane (gradient from 20:80 to 30:70) to provide the desiredproduct as a white solid (1.2 g, 56% yield). LCMS (M+H)⁺ m/z 333, 335.

2.2-Fluoro-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazolin-4(3H)-one

A mixture of 3-(3-bromo-2-methylphenyl)-6-fluoroquinazolin-4(3H)-one(1.2 g, 3.60 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.372 g,5.40 mmol), potassium acetate (1.061 g, 10.81 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complexwith CH₂Cl₂ (0.147 g, 0.180 mmol) in dioxane (15 mL) was heated in asealed vial at 110° C. for 3 h. The mixture was cooled to roomtemperature, diluted with EtOAc and washed with water. The organic phasewas filtered, dried and concentrated. The residue was purified by columnchromatography on silica gel (40 g) eluting with EtOAc-hexane (gradientfrom 20:80 to 40:60) to provide6-Fluoro-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazolin-4(3H)-oneas a white glassy foam (1.25 g, 91% yield). LCMS (M+H)⁺ m/z 380.9.

Intermediate 1 was used in the preparation of Example 112 in Table 3.

Intermediate 26-Fluoro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoindolin-1-one

1. 2-(Bromomethyl)-5-fluorobenzoic acid

A suspension of 5-fluoro-2-methylbenzoic acid (500 mg, 3.24 mmol),N-bromosuccinimide (606 mg, 3.41 mmol) and benzoyl peroxide (47 mg,0.195 mmol) in tetrachloromethane (10 mL) was heated at 78° C. for 4 h.The hot mixture was filtered and the filtrate was concentrated toprovide crude 2-(bromomethyl)-5-fluorobenzoic acid as a white solid (730mg), used without further purification. ¹H NMR (400 MHz, chloroform-d) δ7.81 (1 H, dd, J=9.2, 2.9 Hz), 7.50 (1 H, dd, J=8.5, 5.4 Hz), 7.23-7.30(1 H, m), 4.98 (2 H, s).

2. N-(3-Bromo-2-methylphenyl)-2-(bromomethyl)-5-fluorobenzamide

A solution of crude 2-(bromomethyl)-5-fluorobenzoic acid (3.05 g, 13.1mmol) in CH₂Cl₂ (50 mL) was treated with oxalyl chloride (1.66 g, 13.1mmol) and 6 drops of DMF. The mixture was stirred at room temperaturefor 1 h, and then was concentrated. The residue was dissolved in CH₂Cl₂(50 mL) and treated with 3-bromo-2-methylaniline (1.705 g, 9.16 mmol).The mixture was stirred at room temperature for 1 h, and then TEA (2.19mL, 15.7 mmol) was added in portions. The mixture was stirred at roomtemperature for 2 h, then was diluted with CH₂Cl₂ (100 mL), washed withNaHCO₃ (aq) and water, dried and concentrated. The residue wastriturated with CH₂Cl₂ to provide the desired product as a white solid(0.9 g). The mother liquor was concentrated and the residue was againtriturated with CH₂Cl₂ to provide additional desired product as a whitesolid (0.46 g). The mother liquor was concentrated and the residue waspurified by column chromatography on silica gel, eluting withEtOAc-hexane (gradient from 0:100 to 30:70) to provide additionaldesired product as a pink solid (1.18 g) for a total of 2.54 g (48%yield). LCMS (M+H)⁺ m/z 400, 402, 404.

3. 2-(3-Bromo-2-methylphenyl)-6-fluoroisoindolin-1-one

A mixture ofN-(3-bromo-2-methylphenyl)-2-(bromomethyl)-5-fluorobenzamide (2.54 g,6.33 mmol) and sodium tert-butoxide (0.913 g, 9.50 mmol) in THF (80 mL)was stirred at room temperature for 30 min. The mixture was diluted withwater and extracted with twice with CH₂Cl₂. The combined organic phaseswere washed with water, dried and concentrated. The residue was purifiedby column chromatography on silica gel, eluting with EtOAc-hexane toprovide the desired product as a white solid (1.18 g, 58% yield). LCMS(M+H)+ m/z 320, 322.

4.6-Fluoro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoindolin-1-one

A mixture of 2-(3-bromo-2-methylphenyl)-6-fluoroisoindolin-1-one (1.367g, 4.27 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.301 g,5.12 mmol), potassium acetate (0.838 g, 8.54 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complexwith CH₂Cl₂ (0.105 g, 0.128 mmol) in dioxane (30 mL) and DMSO (6 mL) wasdegassed with nitrogen and heated in equal portions in two sealed vialsat 90° C. overnight. The mixtures were cooled to room temperature andcombined, diluted with CH₂Cl₂ and washed with water. The aqueous phasewas extracted twice with CH₂Cl₂, and the combined organic phases weredried and concentrated. The residue was purified by columnchromatography on silica gel (52 g) eluting with EtOAc-hexane (gradientfrom 0:100 to 50:50) to provide the desired product as a white solid(1.35 g, 86% yield). LCMS (M+H)⁺ m/z 368.1.

Intermediates 4, 5, 6 in Table 4 were prepared in the same manner asIntermediate 2 was prepared.

Intermediate 2 was used in the preparation of Examples 108 and 113 inTable 3. Intermediate 3, prepared in the same manner as Intermediate 1,was used in the preparation of Examples 42-51 and 114-117. Intermediate4 was used to prepare Example 112. Intermediate 6 was used to prepareExample 113.

TABLE 4 Intermediate No. Structure (M + H)⁺ 1

380.9 2

368.1 3

363.2 4

381.2 5

393.1 6

381.1

What is claimed is:
 1. A compound according to formula (I):

or an enantiomer, a diastereomer, a stereoisomer thereof, wherein X isCR³ or N; Y is CR³ or N; Z is CD¹ or N; W is CD² or N; — is an optionalbond; provided when the two optional bonds are absent, Z is CHD¹, W isND² or Z is ND¹, W is CHD²; wherein said compound of formula (I) isselected from:

A is C₃₋₁₀ carbocycle substituted with 0-5 B or C₆₋₁₀ mono- or bicyclicaryl substituted with 0-5 B; B is R¹, halogen, cyano, nitro, —OR¹,—C(═O)R¹, —C(═O)OR¹, —C(═O)NR¹¹R¹, —S(═O)₂R¹, —NR¹C(═O)R¹,—NR¹¹C(═O)NR¹¹R¹, —NR¹¹C(═O)OR¹, —N(C(═O)OR¹)₂, —NR¹¹S(═O)₂R¹,—N(S(═O)₂R¹)₂, or —NR¹¹R¹; R¹ is hydrogen, C₁₋₆ alkyl substituted with0-3 R^(1a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(1a),C₂₋₆ alkynyl substituted with 0-3 R^(1a), C₃₋₁₀ cycloalkyl substitutedwith 0-5 R^(1a), C₆₋₁₀ aryl substituted with 0-5 R^(1a), a 5-10 memberedheterocyclyl containing 1-4 heteroatoms selected from N, O, and S,substituted with 0-5 R^(1a), or a 5-10 membered heteroaryl containing1-4 heteroatoms selected from N, O, and S, substituted with 0-5 R^(1a);R^(1a) is hydrogen, ═O, F, Cl, Br, OCF₃, CF₃, CHF₂, CN, NO₂,—(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(p)R^(c), —S(O)R^(c), S(O)₂R^(c), C₁₋₆ alkyl substitutedwith 0-2 R^(a), C₁₋₆ haloalkyl, —(CH₂)_(r)-3-14 membered carbocyclesubstituted with 0-1 R^(a), or —(CH₂)_(r)-5-7 membered heterocyclecomprising carbon atoms and 1-4 heteroatoms selected from N, O, andS(O)_(p) substituted with 0-1 R^(a); D¹ and D² are independently R²,halogen, —(C(R¹¹)₂)_(r)R², —OR², —C(═O)R², —C(═O)OR², —C(═O)NR¹¹R²,—S(═O)₂R², —S(═O)R², —SR², —NR¹¹C(═O)R², —NR¹¹C(═O)NR¹¹R²,—NR¹¹C(═O)OR², —NR¹¹S(═O)₂R², —NR¹¹R², —C(═O)NR¹¹OR², —OC(═O)OR²,—OC(═O)R², or —CH═N—OH; alternatively D¹ and D² join to form —O—CH₂—O—;D³ is hydrogen, halogen, C₁₋₃ alkyl, C₁₋₃ alkoxy, or CN; R² is hydrogen,C₁₋₆ alkyl substituted with 0-3 R^(2a), C₂₋₆ alkenyl substituted with0-3 R^(2a), C₂₋₆ alkynyl substituted with 0-3 R^(2a), C₃₋₁₀ cycloalkylsubstituted with 0-5 R^(2a), C₆₋₁₀ aryl substituted with 0-5 R^(2a), a5-10 membered heterocyclyl containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-5 R^(2a), or a 5-10 membered heteroarylcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-5 R^(2a); R^(2a) is hydrogen, ═O, F, Cl, Br, OCF₃, CN, NO₂,—(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(p)R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substitutedwith 0-2 R^(a), C₁₋₆ haloalkyl, —(CH₂)_(r)-3-14 membered carbocyclesubstituted with 0-1 R^(a), or —(CH₂)_(r)-5-7 membered heterocyclecomprising carbon atoms and 1-4 heteroatoms selected from N, O, andS(O)_(p) substituted with 0-2 R^(a); R³ is hydrogen or C₁₋₆ alkyl; R¹¹is independently hydrogen or C₁₋₄ alkyl substituted with 0-1 R^(f),—CH₂-phenyl, or —(CH₂)_(r)-5-7 membered heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, O, and S(O)_(p);alternatively, R¹¹ along with another R¹¹, R¹, or R² on the samenitrogen atom may join to form an optionally substituted azetidinyl,pyrrolidinyl, piperidinyl, morpholinyl, or 4-(C₁₋₆ alkyl)piperazinyl;R^(a) is hydrogen, F, Cl, Br, OCF₃, CF₃, CHF₂, CN, NO₂,—(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(p)R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substitutedwith 0-1 R^(f), C₁₋₆ haloalkyl, —(CH₂)_(r)-3-14 membered carbocycle, or—(CH₂)_(r)-5-7 membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), alternatively two R^(a) onadjacent or the same carbon atom form a cyclic acetal of the formula—O—(CH₂)_(n)—O—, or —O—CF₂—O—, wherein n is selected from 1 or 2; R^(b)is hydrogen, C₁₋₆ alkyl substituted with 0-2 R^(d), C₁₋₆ haloalkyl, C₃₋₆cycloalkyl substituted with 0-2 R^(d), or —(CH₂)_(r)-phenyl substitutedwith 0-2 R^(d); R^(c) is C₁₋₆ alkyl substituted with 0-1 R^(f), C₃₋₆cycloalkyl, or —(CH₂)_(r)-phenyl substituted with 0-1 R^(f); R^(d) ishydrogen, F, Cl, Br, OCF₃, CF₃, CN, NO₂, —OR^(e), —(CH₂)_(r)(O)R^(c),—NR^(e)R^(e), —NR^(e)C(O)OR^(c), C₁₋₆ alkyl, or —(CH₂)_(r)-phenyl; R^(e)is hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, or —(CH₂)_(r)-phenyl; R^(f) ishydrogen, halo, NH₂, OH, or OCH₃; r is 0, 1, 2, 3, or 4; and p is 0, 1,or
 2. 2. The compound according to claim 1, having formula (Ia), (Ib),or (Ic):

wherein A is C₆₋₁₀ mono- or bicyclic aryl substituted with 0-5 B.
 3. Thecompound according to claim 1, having formula (Id) or (Ie):

wherein A is C₆₋₁₀ mono- or bicyclic aryl substituted with 0-5 B.
 4. Thecompound according to claim 1, wherein formula (I) is formula (If) or(Ig):

wherein A is C₆₋₁₀ mono- or bicyclic aryl substituted with 0-5 B.
 5. Thecompound according to claim 1, wherein D¹ and D² are independently R²,—(CH₂)_(r)R², —OR², —C(═O)R², —C(═O)OR², —C(═O)NR¹¹R², —S(O)₂R²,—S(O)R², —SR², —NR¹¹C(O)R², —NR¹¹C(O)NR¹¹R², —NR¹¹C(═O)OR²,—NR¹¹S(═O)₂R², or —NR¹¹R²; R² is hydrogen, C₁₋₆ alkyl substituted with0-3 R^(2a), C₂₋₆ alkenyl substituted with 0-3 R^(2a), C₃₋₁₀ cycloalkylsubstituted with 0-4 R^(2a), —C₆₋₁₀ aryl substituted with 0-4 R^(2a), a5-10 membered heterocyclyl containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-4 R^(2a), or a 5-10 membered heteroarylcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-4 R^(2a); R^(2a) is hydrogen, ═O, F, Cl, Br, OCF₃, CF₃, CHF₂, CN, NO₂,OR^(b), SR^(b), —C(O)R^(b), —C(O)OR^(b), —OC(O)R^(b), —NR¹¹R¹¹,—C(O)NR¹¹R¹¹, —NR^(b)C(O)R^(c), —NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹,—S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆alkyl substituted with 0-2 R^(a), —(CH₂)_(r)-3-14 membered carbocyclesubstituted with 0-1 R^(a), wherein the carbocycle is cyclopropyl,cyclobutyl, cyclopentyl or cyclohexyl; or —(CH₂)_(r)-5-7 memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,O, and S(O)_(p) substituted with 0-2 R^(a); and r is 0, 1, or
 2. 6. Thecompound according claim 1, or an enantiomer, a diastereomer, astereoisomer thereof, wherein said compound of formula (I) is selectedfrom:

B¹ is hydrogen, halogen, cyano, nitro, —OH, or C₁₋₆ alkyl substitutedwith 0-3 R^(1a); B² is R¹, —C(═O)R¹, —C(═O)OR¹, —C(═O)NR¹¹R¹, —S(═O)₂R¹,—NR¹¹C(═O)R¹, —NR¹¹C(═O)NR¹¹R¹, —NR¹¹C(═O)OR¹, —N(C(═O)OR¹)₂,—NR¹¹S(═O)₂R¹, —N(S(═O)₂R¹)₂, or —NR¹¹R¹; R¹ is hydrogen, C₁₋₆ alkylsubstituted with 0-3 R^(1a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substitutedwith 0-3 R^(1a), C₂₋₆ alkynyl substituted with 0-3 R^(1a), C₃₋₁₀cycloalkyl substituted with 0-5 R^(1a), C₆₋₁₀ aryl substituted with 0-5R^(1a), a 5-10 membered heterocyclyl containing 1-4 heteroatoms selectedfrom N, O, and S, substituted with 0-5 R^(1a), or a 5-10 memberedheteroaryl containing 1-4 heteroatoms selected from N, O, and S,substituted with 0-5 R^(1a); R^(1a) is hydrogen, ═O, F, Cl, Br, OCF₃,CF₃, CHF₂, CN, NO₂, —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b),—(CH₂)_(r)C(O)R^(b), —(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b),—(CH₂)_(r)NR¹¹R¹¹, —(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(p)R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substitutedwith 0-2 R^(a), C₁₋₆ haloalkyl, —(CH₂)_(r)-3-14 membered carbocyclesubstituted with 0-1 R^(a), or —(CH₂)_(r)-5-7 membered heterocyclecomprising carbon atoms and 1-4 heteroatoms selected from N, O, andS(O)_(p) substituted with 0-1 R^(a); D¹ and D² are independently R²,halogen, —C(R¹¹)₂)_(r)R², —(C(R¹¹)₂)_(r)OR², —C(═O)R², —C(═O)OR²,—C(═O)NR¹¹R², —S(═O)₂R², —S(═O)R², —SR², —NR¹¹C(═O)R², —NR¹¹C(═O)NR¹¹R²,—NR¹¹C(═O)OR², —NR¹¹S(═O)₂R², —NR¹¹R², —C(═O)NR¹¹OR², —OC(═O)OR²,—OC(═O)R², or —CH═N—OH; alternatively D¹ and D² join to form —O—CH₂—O—;D³ is hydrogen, halogen, C₁₋₃ alkyl, C₁₋₃ alkoxy, or CN; R² is hydrogen,C₁₋₆ alkyl substituted with 0-3 R^(2a), C₂₋₆ alkenyl substituted with0-3 R^(2a), C₂₋₆ alkynyl substituted with 0-3 R^(2a), C₃₋₁₀ cycloalkylsubstituted with 0-5 R^(2a), C₆₋₁₀ aryl substituted with 0-5 R^(2a), a5-10 membered heterocyclyl containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-5 R^(2a), or a 5-10 membered heteroarylcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-5 R^(2a); R^(2a) is hydrogen, ═O, F, Cl, Br, OCF₃, CN, NO₂,—(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(p)R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substitutedwith 0-2 R^(a), C₁₋₆ haloalkyl, —(CH₂)_(r)-3-14 membered carbocyclesubstituted with 0-1 R^(a), or —(CH₂)_(r)-5-7 membered heterocyclecomprising carbon atoms and 1-4 heteroatoms selected from N, O, andS(O)_(p) substituted with 0-2 R^(a); R¹¹ is independently hydrogen orC₁₋₄ alkyl substituted with 0-1 R^(f), —CH₂-phenyl, or —(CH₂)_(r)-5-7membered heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p); alternatively, R¹¹ along with anotherR¹¹, R¹, or R² on the same nitrogen atom may join to form an optionallysubstituted azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, or4-(C₁₋₆ alkyl)piperazinyl; R³ is hydrogen or C₁₋₆ alkyl; R^(a) ishydrogen, F, Cl, Br, OCF₃, CF₃, CHF₂, CN, NO₂, —(CH₂)_(r)OR^(b),—(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b), —(CH₂)_(r)C(O)OR^(b),—(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹, —(CH₂)_(r)C(O)NR¹¹R¹¹,—(CH₂)_(r)NR^(b)C(O)R^(c), —(CH₂)_(r)NR^(b)C(O)OR^(c),—NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c),—S(O)R^(c),—S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-1 R^(f), C₁₋₆ haloalkyl,—(CH₂)_(r)-3-14 membered carbocycle, or —(CH₂)_(r)-5-7 memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,O, and S(O)_(p); alternatively two R^(a) on adjacent or the same carbonatom form a cyclic acetal of the formula —O—(CH₂)_(n)—O—, or —O—CF₂—O—,wherein n is selected from 1 or 2; R^(b) is hydrogen, C₁₋₆ alkylsubstituted with 0-2 R^(d), C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl substitutedwith 0-2 R^(d), or —(CH₂)_(r)-phenyl substituted with 0-2 R^(d); R^(c)is C₁₋₆ alkyl substituted with 0-1 R^(f), C₃₋₆ cycloalkyl, or—(CH₂)_(r)-phenyl substituted with 0-1 R^(f); R^(d) is hydrogen, F, Cl,Br, OCF₃, CF₃, CN, NO₂, —OR^(e), —(CH₂)_(r)C(O)R^(c), —NR^(e)R^(e),—NR^(e)C(O)OR^(c), C₁₋₆ alkyl, or —(CH₂)_(r)-phenyl; R^(e) is hydrogen,C₁₋₆ alkyl, C₃₋₆ cycloalkyl, or —(CH₂)_(r)-phenyl; R^(f) is hydrogen,halo, NH₂, OH, or OCH₃; r is 0, 1, 2, 3, or 4; and p is 0, 1, or
 2. 7.The compound according to claim 6 having formula (IIa), (IIb), or (IIc):


8. The compound according to claim 6 having formula (IId) or (IIe):


9. The compound according to claim 6 having formula (IIf) or (IIg):


10. The compound according to claim 6 wherein B¹ is C₁₋₄ alkyl orhalogen; B² is R¹, halogen, C₁₋₄ alkyl, —NR¹¹C(═O)R¹, —NR¹¹C(═O)OR¹,—NR¹¹C(═O)NR¹¹R¹, or —NR¹¹R¹; R¹ is hydrogen, C₁₋₄ alkyl, indane orphenyl substituted with 0-3 R^(1a), a 5-10 membered heterocyclylcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-3 R^(1a), or a 5-10 membered heteroaryl containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(1a), wherein theheterocyclyl or heteroaryl is selected from

R^(1a) is F, Cl, Br, —NR¹¹, R¹¹, —OR^(b), or C₁₋₆ alkyl substituted with0-1 R^(a); D¹ and D² are independently R², halogen, —OR², —C(═O)R²,—C(═O)OR², —C(═O)NR¹¹R², —NR¹¹C(═O)R², —NR¹¹S(═O)₂R², —SR², —S(═O)R²,—S(═O)₂R², or —NR¹¹R²; alternatively D¹ and D² join to form —O—CH₂—O—;R² is hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(2a), a 5-10 memberedheterocyclyl containing 1-4 heteroatoms selected from N, O, and S,substituted with 0-3 R^(2a), wherein the heterocyclyl is selected frompyrimidinyl, morpholinyl, piperidinyl, pyrrolidinyl, pyridinyl,tetrahydropyranyl, or tetrahydrofuranyl; R^(2a) is hydrogen, CN, C₁₋₆alkyl, —N(CH₃)₂ or —OR^(b); R¹¹ is independently hydrogen, C₁₋₄ alkyl,or —CH₂-phenyl; R^(a) is hydrogen, F, Cl, Br, OCF₃, CF₃, CHF₂, CN, NO₂,—OR^(b), —SR^(b), —C(O)R^(b), —C(O)OR^(b), —OC(O)R^(b), —NR¹¹R¹¹,—C(O)NR¹¹R¹¹, —NR^(b)C(O)R^(c), —NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹,—S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆alkyl substituted with 0-1 R^(f), C₁₋₆ haloalkyl, —(CH₂)_(r)-3-6membered carbocycle, or —(CH₂)_(r)-5-7 membered heterocycle comprisingcarbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p),wherein the heterocycle is pyrrolidinyl, pyrrolyl, pyrazolyl,imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furyl,thienyl, pyridyl, pyrazinyl, pyrimidinyl, morpholinyl, thiamorpholinyl,triazolyl, indolyl, benzothiazolyl, benzoxazolyl, benzothienyl,quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, benzimidazolyl,benzopyranyl, benzofuryl, benzisothiazolyl, benzisoxazolyl,benzodiazinyl, or benzofurazanyl; R^(b) is hydrogen, C₁₋₄ alkylsubstituted with 0-2 R^(d), C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl substitutedwith 0-2 R^(d), or —(CH₂)_(r)-phenyl substituted with 0-2 R^(d); R^(c)is C₁₋₄ alkyl substituted with 0-1 R^(f), C₃₋₆ cycloalkyl, or—(CH₂)_(r)-phenyl substituted with 0-1 R^(f); R^(d) is hydrogen, F, Cl,Br, OCF₃, CF₃, CN, NO₂, —OR^(e), —C(O)R^(c), —NR^(e)R^(e),—NR^(e)C(O)OR^(c), C₁₋₆ alkyl, or —(CH₂)_(r)-phenyl; R^(e) is hydrogen,C₁₋₄alkyl, C₃₋₆ cycloalkyl, or —(CH₂)_(r)-phenyl; R^(f) is hydrogen,halo, or NH₂; and r is 0 or
 1. 11. The compound according to claim 10,wherein R^(a) is hydrogen, F, Cl, Br, OCF₃, CF₃, CHF₂, CN, NO₂, —OR^(b),—SR^(b), —C(O)R^(b), —C(O)OR^(b), —OC(O)R^(b), —NR¹¹R¹¹, —C(O)NR¹¹R¹¹,—NR^(b)C(O)R^(c), —NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹,—S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆alkyl, C₁₋₆ haloalkyl, —(CH₂)_(r)-3-6 membered carbocycle phenyl, or—(CH₂)_(r)-5-7 membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein the heterocycle isthiazolyl, pyridinyl, piperidinyl, morpholinyl, piperazinyl,pyrrolidinyl, or pyrrolidin-one, R^(b) is hydrogen, C₁₋₄ alkylsubstituted with 0-2 R^(d), C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl substitutedwith 0-2 R^(d), or —(CH₂)_(r)-phenyl substituted with 0-2 R^(d); R^(c)is C₁₋₄ alkyl, C₃₋₆ cycloalkyl, or —(CH₂)_(r)-phenyl; R^(d) is hydrogen,F, Cl, Br, OCF₃, CF₃, CN, NO₂, —OR^(e), —C(O)R^(c), —NR^(e)R^(e),—NHC(O)OR^(c), C₁₋₄ alkyl, or —(CH₂)_(r)-phenyl; and R^(e) is hydrogen,C₁₋₄ alkyl, C₃₋₆ cycloalkyl, or —(CH₂)_(r)-phenyl.
 12. The compoundaccording to claim 10 wherein B¹ is methyl or fluorine; B² is hydrogen,R^(1b), —NR¹¹C(═O)R^(1c), —NR¹¹C(═O)NR¹¹R^(1d), or —NR¹¹R^(1e); R^(1b)is

any of which are substituted with 0-3 R^(1a); R^(1c) is C₁₋₆ alkyl,

any of which are substituted with 0-2 R^(a); R^(1d) is phenylsubstituted with 0-1 R^(1a); R^(1e) is quinazolinyl substituted with 0-1R^(1a); R^(1a) is selected from hydrogen, F, Cl, CN, methyl, ethyl, CF₃,OH, and O-methyl; D¹ and D² are independently selected from R², F, Cl,Br, —OR², —C(═O)R², —C(═O)OR², —C(═O)NR¹¹R², —S(═O)₂R², —S(═O)R², —SR²,—NR¹¹C(═O)R², —NR¹¹S(═O)₂R², and —NR¹¹R²; R² is hydrogen, C₁₋₆ alkylsubstituted with 0-3 R^(2a), piperazinyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperidinyl,pyridinyl, imidazolyl, pyrazinyl, or pyrimidinyl, any of which aresubstituted with 0-3 R^(2a); R^(2a) is hydrogen, CN, —OR^(b), ormorpholinyl; R¹¹ is hydrogen or C₁₋₄ alkyl; R^(a) is hydrogen, F, Cl,C₁₋₄ alkyl, —OR^(b), —NR¹¹R¹¹, imidazolyl, or morpholinyl; and R^(b) ishydrogen or C₁₋₆ alkyl.
 13. A pharmaceutical composition comprising oneor more compounds according to claim 1 and a pharmaceutically acceptablecarrier or diluent.
 14. A method for treating a disease comprising theadministration to a subject in need thereof a therapeutically-effectiveamount of at least one compound according toclaim 1, wherein saiddisease is selected from systemic lupus erythematosus (SLE), rheumatoidarthritis, multiple sclerosis (MS), or transplant rejection.
 15. Amethod of inhibiting Bruton's tyrosine kinase (Btk) comprisingadministering to a subject in need thereof a therapeutically effectiveamount of at least one compound according to claim 1, wherein saiddisease is selected from systemic lupus erythematosus (SLE), rheumatoidarthritis, multiple sclerosis (MS), or transplant rejection.